Pharmaceutical composition for treating tumors

Abstract

The invention belongs to the field of biological medicines, and relates to a medicine composition for treating tumors, which comprises an anti-CD40 antibody and a second therapeutic agent. In addition, the invention also provides application of the anti-CD40 antibody and the second therapeutic agent in preparation of medicines for treating tumors. Wherein the second therapeutic agent is selected from a chemotherapeutic drug or an anti-PD-1 antibody or an antigen-binding fragment thereof.

Description

Technical Field

[0001] This application belongs to the field of biomedicine, and specifically relates to the use of anti-CD40 antibodies and second therapeutic agents for treating tumors. Background Art

[0002] Soft tissue sarcoma is a group of rare connective tissue solid tumors, accounting for about 1% of all adult malignancies, but more common in childhood malignancies, accounting for about 15 - 20%. According to the World Health Organization (WHO) classification, soft tissue sarcoma includes at least 50 different histological subtypes. Among them, liposarcoma accounts for about 20% of soft tissue sarcomas and is the most common pathological type of soft tissue sarcoma, which is divided into five subtypes: well-differentiated liposarcoma, dedifferentiated liposarcoma, myxoid liposarcoma, pleomorphic liposarcoma, and myxoid pleomorphic liposarcoma. Among them, well-differentiated liposarcoma and dedifferentiated liposarcoma are the most common clinically; leiomyosarcoma accounts for 15 - 20% of all soft tissue sarcomas; pleomorphic soft tissue sarcoma is one of the most common pathological types of soft tissue sarcoma, accounting for about 10% of adult soft tissue sarcomas. For soft tissue sarcomas that cannot be surgically resected or have metastasized, current treatment methods are limited, the overall prognosis of chemotherapy is poor, the median overall survival is short, and some targeted drugs show certain therapeutic effects in subtypes of soft tissue sarcoma, but for patients with soft tissue sarcoma without specific therapeutic targets, the clinical benefit is limited. There is an urgent need for new breakthroughs to improve the cure rate of patients with soft tissue sarcoma.

[0003] In recent years, there are nearly 20,000 new cases of melanoma every year, and the incidence rate is increasing year by year. Moreover, most melanomas are in the middle and advanced stages at the time of diagnosis, causing great harm. For patients with inoperable melanoma, treatment methods include targeted therapies such as BRAF inhibitors, mitogen-activated protein kinase kinase (MEK) inhibitors, tyrosine kinase (TKI) inhibitors, etc., and systemic chemotherapies such as dacarbazine, temozolomide, taxanes, platinum-based drugs, etc. However, targeted therapy is only applicable to patients with specific gene mutations, and the effective rate of systemic chemotherapy is low, only reaching 10 - 15%. Therefore, there is an urgent clinical need to improve the treatment effective rate of advanced melanoma.

[0004] CD40 is a type I transmembrane protein present on the surface of antigen-presenting cells (APCs) in the immune system and is also expressed after activation of other hematopoietic cells (such as T cells). The homologous ligand of CD40 is CD154 (TNFSF5 / CD40L), a 39 kDa type II transmembrane protein. The expression of CD40L is usually induced and restricted to cells of the hematopoietic system, such as platelets, granulocytes, activated T cells, activated B cells, and activated natural killer (NK) cells, but endothelial cells and smooth muscle cells also have weak expression. A large number of studies have confirmed that CD40 - CD40L plays a role in CD8 in the immune response +The function of cytotoxic T lymphocytes (CTL) plays a crucial role and is essential for the adaptive immune response.

[0005] The development of a new generation of CD40 agonists provides more options for the clinical treatment of soft tissue sarcoma and melanoma. Summary of the Invention

[0007] In one aspect, the present application provides a pharmaceutical combination comprising an anti-CD40 antibody or an antigen-binding fragment thereof and a second therapeutic agent. In some embodiments, the second therapeutic agent comprises an anti-tumor drug.

[0008] In some embodiments, the second therapeutic agent comprises an anti-PD-1 antibody or an antigen-binding fragment thereof. In some specific embodiments, the anti-PD-1 antibody or an antigen-binding fragment thereof is penpulimab.

[0009] In some embodiments, the second therapeutic agent comprises a chemotherapeutic drug. In some embodiments, the chemotherapeutic drug comprises anthracyclines. In some specific embodiments, the anthracyclines comprise doxorubicin.

[0010] In some specific embodiments, the pharmaceutical combination of the present application comprises an anti-CD40 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., penpulimab). In some other specific embodiments, the pharmaceutical combination of the present application comprises an anti-CD40 antibody or an antigen-binding fragment thereof and anthracyclines (e.g., doxorubicin).

[0011] In another aspect, the present application also provides a method for treating a tumor in a subject, which comprises administering to the subject a therapeutically effective amount of the pharmaceutical combination of the present application. Additionally, the present application also provides the use of the pharmaceutical combination of the present application in the preparation of a drug for treating a tumor in a subject. Additionally, the present application also provides the use of the pharmaceutical combination of the present application for treating a tumor in a subject.

[0012] In another aspect, the present application also provides a method for treating a tumor in a subject, which comprises administering to the subject a therapeutically effective amount of the anti-CD40 antibody or an antigen-binding fragment thereof and a second therapeutic agent of the present application. Additionally, the present application also provides the use of the anti-CD40 antibody or an antigen-binding fragment thereof and a second therapeutic agent of the present application in the preparation of a drug for treating a tumor in a subject. Additionally, the present application also provides the use of the anti-CD40 antibody or an antigen-binding fragment thereof and a second therapeutic agent of the present application for treating a tumor in a subject. Additionally, the present application also provides the use of the anti-CD40 antibody or an antigen-binding fragment thereof of the present application in the preparation of a drug for combined use with a second therapeutic agent for treating a tumor.

[0013] In some specific embodiments, the present application also provides a method for treating tumors in a subject, which comprises administering to the subject a therapeutically effective amount of the anti-CD40 antibody or its antigen-binding fragment of the present application and an anti-PD-1 antibody or its antigen-binding fragment (e.g., penpulimab). In some specific embodiments, the present application also provides a method for treating tumors in a subject, which comprises administering to the subject a therapeutically effective amount of the anti-CD40 antibody or its antigen-binding fragment of the present application and a chemotherapeutic agent (e.g., anthracyclines). In some specific embodiments, the present application also provides a method for treating tumors in a subject, which comprises administering to the subject a therapeutically effective amount of the anti-CD40 antibody or its antigen-binding fragment of the present application and anthracyclines (e.g., doxorubicin).

[0014] In some specific embodiments, the present application provides the use of the anti-CD40 antibody or its antigen-binding fragment of the present application and an anti-PD-1 antibody or its antigen-binding fragment (e.g., penpulimab) in the preparation of a medicament for treating tumors in a subject. In some specific embodiments, the present application provides the use of the anti-CD40 antibody or its antigen-binding fragment of the present application and a chemotherapeutic agent (e.g., anthracyclines) in the preparation of a medicament for treating tumors in a subject. In some specific embodiments, the present application provides the use of the anti-CD40 antibody or its antigen-binding fragment of the present application and anthracyclines (e.g., doxorubicin) in the preparation of a medicament for treating tumors in a subject.

[0015] In some specific embodiments, the present application also provides the use of the anti-CD40 antibody or its antigen-binding fragment of the present application and an anti-PD-1 antibody or its antigen-binding fragment (e.g., penpulimab) for treating tumors in a subject. In some specific embodiments, the present application also provides the use of the anti-CD40 antibody or its antigen-binding fragment of the present application and a chemotherapeutic agent (e.g., anthracyclines) for treating tumors in a subject. In some specific embodiments, the present application also provides the use of the anti-CD40 antibody or its antigen-binding fragment of the present application and anthracyclines (e.g., doxorubicin) for treating tumors in a subject.

[0016] In some specific embodiments, the present application also provides the use of the anti-CD40 antibody or its antigen-binding fragment of the present application in the preparation of a medicament for combined use with an anti-PD-1 antibody or its antigen-binding fragment (e.g., penpulimab) for treating tumors. In some specific embodiments, the present application also provides the use of the anti-CD40 antibody or its antigen-binding fragment of the present application in the preparation of a medicament for combined use with a chemotherapeutic agent (e.g., anthracyclines) for treating tumors. In some specific embodiments, the present application also provides the use of the anti-CD40 antibody or its antigen-binding fragment of the present application in the preparation of a medicament for combined use with anthracyclines (e.g., doxorubicin) for treating tumors.

[0017] On the other hand, the present application also provides the use of the anti-CD40 antibody of the present application or an antigen-binding fragment thereof in the preparation of a medicament for treating a tumor of a subject, wherein the medicament is for use in combination with a second therapeutic agent of the present application. In some specific embodiments, the present application also provides the use of the anti-CD40 antibody of the present application or an antigen-binding fragment thereof in the preparation of a medicament for treating a tumor of a subject, wherein the medicament is for use in combination with an anti-PD-1 antibody of the present application or an antigen-binding fragment thereof (e.g., penpulimab). In some specific embodiments, the present application also provides the use of the anti-CD40 antibody of the present application or an antigen-binding fragment thereof in the preparation of a medicament for treating a tumor of a subject, wherein the medicament is for use in combination with a chemotherapeutic drug (e.g., anthracyclines). In some specific embodiments, the present application also provides the use of the anti-CD40 antibody of the present application or an antigen-binding fragment thereof in the preparation of a medicament for treating a tumor of a subject, wherein the medicament is for use in combination with anthracyclines (e.g., doxorubicin).

[0018] On the other hand, the present application also provides a kit for treating a tumor, which comprises the drug combination of the present application. In some embodiments, the kit comprises an anti-CD40 antibody or an antigen-binding fragment thereof and a second therapeutic agent, and instructions for using the anti-CD40 antibody or an antigen-binding fragment thereof and the second therapeutic agent in combination to treat a tumor. In some specific embodiments, the kit comprises an anti-CD40 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., penpulimab), and instructions for using the anti-CD40 antibody or an antigen-binding fragment thereof and the anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., penpulimab) in combination to treat a tumor. In some specific embodiments, the kit comprises an anti-CD40 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof, and instructions for using the anti-CD40 antibody or an antigen-binding fragment thereof and a chemotherapeutic drug (e.g., anthracyclines) in combination to treat a tumor. In some specific embodiments, the kit comprises an anti-CD40 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof, and instructions for using the anti-CD40 antibody or an antigen-binding fragment thereof and anthracyclines (e.g., doxorubicin) in combination to treat a tumor.

[0019] In some embodiments, the tumor is a solid tumor. In some specific embodiments, the tumor is a soft tissue sarcoma. In some specific embodiments, the tumor is melanoma. Detailed Description of the Invention

[0021] Anti-CD40 antibody or its antigen-binding fragment and anti-PD-1 antibody or its antigen-binding fragment

[0022] In one aspect, the present application provides a drug combination comprising an anti-CD40 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof. In some specific embodiments, the anti-PD-1 antibody or an antigen-binding fragment thereof is penpulimab.

[0023] In some embodiments, the drug combination is packaged in the same kit, and the kit further includes instructions for using the anti-CD40 antibody or an antigen-binding fragment thereof and the anti-PD-1 antibody or an antigen-binding fragment thereof in combination for treating tumors. In other embodiments, the anti-CD40 antibody or an antigen-binding fragment thereof and the anti-PD-1 antibody or an antigen-binding fragment thereof in the drug combination are separately packaged in respective cartridges, and the cartridges further include instructions for using the anti-CD40 antibody or an antigen-binding fragment thereof and the anti-PD-1 antibody or an antigen-binding fragment thereof in combination for treating tumors.

[0024] In some embodiments, the anti-CD40 antibody or an antigen-binding fragment thereof and the anti-PD-1 antibody or an antigen-binding fragment thereof are each in the form of a pharmaceutical composition. In some embodiments, the pharmaceutical composition of the anti-CD40 antibody or an antigen-binding fragment thereof is a liquid preparation or a solid preparation. In some specific embodiments, the pharmaceutical composition of the anti-CD40 antibody or an antigen-binding fragment thereof is an injection solution. In some specific embodiments, the pharmaceutical composition of the anti-CD40 antibody or an antigen-binding fragment thereof is a lyophilized preparation. In some embodiments, the pharmaceutical composition of the anti-PD-1 antibody or an antigen-binding fragment thereof is a liquid preparation or a solid preparation. In some specific embodiments, the pharmaceutical composition of the anti-PD-1 antibody or an antigen-binding fragment thereof is an injection solution. In some specific embodiments, the pharmaceutical composition of the anti-PD-1 antibody or an antigen-binding fragment thereof is a lyophilized preparation.

[0025] In some embodiments, the pharmaceutical combination comprises 10 - 800 mg, 20 - 500 mg, 30 - 300 mg, or 60 - 200 mg of an anti - CD40 antibody or an antigen - binding fragment thereof. In some embodiments, the pharmaceutical combination comprises 10 mg, 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg, 620 mg, 640 mg, 660 mg, 680 mg, 700 mg, 720 mg, 740 mg, 760 mg, 780 mg, or 800 mg, or an anti - CD40 antibody or an antigen - binding fragment thereof within the range formed by any of the above values. In some embodiments, the pharmaceutical combination comprises 30 - 300 mg of an anti - CD40 antibody or an antigen - binding fragment thereof. In some embodiments, the pharmaceutical combination comprises 60 - 200 mg of an anti - CD40 antibody or an antigen - binding fragment thereof. In some embodiments, the pharmaceutical combination comprises 60 mg, 100 mg, 120 mg, 180 mg, 200 mg, 240 mg, or 300 mg of an anti - CD40 antibody or an antigen - binding fragment thereof. In some embodiments, the pharmaceutical combination comprises 60 mg, 100 mg, or 200 mg of an anti - CD40 antibody or an antigen - binding fragment thereof. In some embodiments, the pharmaceutical combination comprises 60 mg of an anti - CD40 antibody or an antigen - binding fragment thereof. In some embodiments, the pharmaceutical combination comprises 100 mg of an anti - CD40 antibody or an antigen - binding fragment thereof. In some specific embodiments, the pharmaceutical combination comprises 200 mg of an anti - CD40 antibody or an antigen - binding fragment thereof.

[0026] In some embodiments, the pharmaceutical combination comprises 10 - 800 mg, 50 - 500 mg, or 100 - 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination comprises 10 mg, 50 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg or 800 mg, or an anti-PD-1 antibody or an antigen-binding fragment thereof in a range formed by any of the above values. In some embodiments, the pharmaceutical combination comprises 100 - 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof. In some specific embodiments, the pharmaceutical combination comprises 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0027] In some embodiments, the drug combination comprises 10 - 800 mg, 20 - 500 mg, 30 - 300 mg, or 60 - 200 mg of an anti-CD40 antibody or an antigen-binding fragment thereof, and 10 - 800 mg, 50 - 500 mg, or 100 - 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug combination comprises 10 mg, 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg, 620 mg, 640 mg, 660 mg, 680 mg, 700 mg, 720 mg, 740 mg, 760 mg, 780 mg, or 800 mg, or an anti-CD40 antibody or an antigen-binding fragment thereof within a range formed by any of the above values, and 10 mg, 50 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, or 800 mg, or an anti-PD-1 antibody or an antigen-binding fragment thereof within a range formed by any of the above values. In some embodiments, the drug combination comprises 30 - 300 mg of an anti-CD40 antibody or an antigen-binding fragment thereof, and 100 - 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug combination comprises 60 - 200 mg of an anti-CD40 antibody or an antigen-binding fragment thereof, and 100 - 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug combination comprises 60 mg, 100 mg, or 200 mg of an anti-CD40 antibody or an antigen-binding fragment thereof, and 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug combination comprises 60 mg of an anti-CD40 antibody or an antigen-binding fragment thereof, and 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug combination comprises 100 mg of an anti-CD40 antibody or an antigen-binding fragment thereof, and 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug combination comprises 200 mg of an anti-CD40 antibody or an antigen-binding fragment thereof, and 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0028] In some embodiments, in the said drug combination, the content of the anti-CD40 antibody or its antigen-binding fragment is a daily dose. In some embodiments, in the said drug combination, the content of the anti-CD40 antibody or its antigen-binding fragment is a once-daily dose.

[0029] In some embodiments, in the said drug combination, the content of the anti-CD40 antibody or its antigen-binding fragment is a uniform dose.

[0030] In some embodiments, in the said drug combination, the content of the anti-CD40 antibody or its antigen-binding fragment is a dose for one treatment cycle, and each treatment cycle is 3 weeks.

[0031] In some embodiments, in the said drug combination, the content of the anti-PD-1 antibody or its antigen-binding fragment is a daily dose. In some embodiments, in the said drug combination, the content of the anti-PD-1 antibody or its antigen-binding fragment is a once-daily dose.

[0032] In some embodiments, in the said drug combination, the content of the anti-PD-1 antibody or its antigen-binding fragment is a uniform dose.

[0033] In some embodiments, in the said drug combination, the content of the anti-PD-1 antibody or its antigen-binding fragment is a dose for one treatment cycle, and each treatment cycle is 3 weeks.

[0034] In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle and comprises 10 - 800 mg, 20 - 500 mg, 30 - 300 mg, or 60 - 200 mg of an anti - CD40 antibody or an antigen - binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle and comprises 10 mg, 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg, 620 mg, 640 mg, 660 mg, 680 mg, 700 mg, 720 mg, 740 mg, 760 mg, 780 mg, or 800 mg, or an anti - CD40 antibody or an antigen - binding fragment thereof within a range formed by any of the above values. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle and comprises 30 - 300 mg of an anti - CD40 antibody or an antigen - binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle and comprises 60 - 200 mg of an anti - CD40 antibody or an antigen - binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle and comprises 60 mg, 100 mg, 120 mg, 180 mg, 200 mg, 240 mg, or 300 mg of an anti - CD40 antibody or an antigen - binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle and comprises 60 mg, 100 mg, or 200 mg of an anti - CD40 antibody or an antigen - binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle and comprises 60 mg of an anti - CD40 antibody or an antigen - binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle and comprises 100 mg of an anti - CD40 antibody or an antigen - binding fragment thereof. In some specific embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle and comprises 200 mg of an anti - CD40 antibody or an antigen - binding fragment thereof.

[0035] In some embodiments, the drug combination is suitable for administration within a single treatment cycle and comprises 10 - 800 mg, 50 - 500 mg, or 100 - 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug combination is suitable for administration within a single treatment cycle and comprises 10 mg, 50 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg or 800 mg, or an anti-PD-1 antibody or an antigen-binding fragment thereof within a range formed by any of the above values. In some embodiments, the drug combination is suitable for administration within a single treatment cycle and comprises 100 - 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof. In some specific embodiments, the drug combination is suitable for administration within a single treatment cycle and comprises 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0036] In some embodiments, the drug combination is suitable for administration within a single treatment cycle and comprises 10 - 800 mg, 20 - 500 mg, 30 - 300 mg, or 60 - 200 mg of an anti - CD40 antibody or an antigen - binding fragment thereof, and 10 - 800 mg, 50 - 500 mg, or 100 - 200 mg of an anti - PD - 1 antibody or an antigen - binding fragment thereof. In some embodiments, the drug combination is suitable for administration within a single treatment cycle and comprises 10 mg, 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg, 620 mg, 640 mg, 660 mg, 680 mg, 700 mg, 720 mg, 740 mg, 760 mg, 780 mg, or 800 mg, or an anti - CD40 antibody or an antigen - binding fragment thereof within a range formed by any of the above values, and 10 mg, 50 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, or 800 mg, or an anti - PD - 1 antibody or an antigen - binding fragment thereof within a range formed by any of the above values. In some embodiments, the drug combination is suitable for administration within a single treatment cycle and comprises 30 - 300 mg of an anti - CD40 antibody or an antigen - binding fragment thereof, and 100 - 200 mg of an anti - PD - 1 antibody or an antigen - binding fragment thereof. In some embodiments, the drug combination is suitable for administration within a single treatment cycle and comprises 60 - 200 mg of an anti - CD40 antibody or an antigen - binding fragment thereof, and 100 - 200 mg of an anti - PD - 1 antibody or an antigen - binding fragment thereof. In some embodiments, the drug combination is suitable for administration within a single treatment cycle and comprises 60 mg, 100 mg, or 200 mg of an anti - CD40 antibody or an antigen - binding fragment thereof, and 200 mg of an anti - PD - 1 antibody or an antigen - binding fragment thereof. In some embodiments, the drug combination is suitable for administration within a single treatment cycle and comprises 60 mg of an anti - CD40 antibody or an antigen - binding fragment thereof, and 200 mg of an anti - PD - 1 antibody or an antigen - binding fragment thereof.In some embodiments, the drug combination is suitable for administration within a single treatment cycle and comprises 100 mg of an anti-CD40 antibody or an antigen-binding fragment thereof, and 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug combination is suitable for administration within a single treatment cycle and comprises 200 mg of an anti-CD40 antibody or an antigen-binding fragment thereof, and 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0037] In some embodiments, the drug combination comprises a pharmaceutical composition of an anti-CD40 antibody or an antigen-binding fragment thereof and a pharmaceutical composition of an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the pharmaceutical composition of the anti-CD40 antibody or an antigen-binding fragment thereof is prepared to be suitable for administering a single dose or multiple doses of 10 - 800 mg, 20 - 500 mg, 30 - 300 mg, or 60 - 200 mg of the anti-CD40 antibody or an antigen-binding fragment thereof to a patient, and the pharmaceutical composition of the anti-PD-1 antibody or an antigen-binding fragment thereof is prepared to be suitable for administering a single dose or multiple doses of 10 - 800 mg, 50 - 500 mg, or 100 - 200 mg of the anti-PD-1 antibody or an antigen-binding fragment thereof to a patient. In some embodiments, the drug combination comprises a pharmaceutical composition of an anti-CD40 antibody or an antigen-binding fragment thereof and a pharmaceutical composition of an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the pharmaceutical composition of the anti-CD40 antibody or an antigen-binding fragment thereof is prepared to be suitable for administering a single dose or multiple doses of 10 mg, 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg, 620 mg, 640 mg, 660 mg, 680 mg, 700 mg, 720 mg, 740 mg, 760 mg, 780 mg, or 800 mg, or a single dose or multiple doses of the anti-CD40 antibody or an antigen-binding fragment thereof within a range formed by any of the above values, and the pharmaceutical composition of the anti-PD-1 antibody or an antigen-binding fragment thereof is prepared to be suitable for administering a single dose or multiple doses of 10 mg, 50 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, or 800 mg, or a single dose or multiple doses of the anti-PD-1 antibody or an antigen-binding fragment thereof within a range formed by any of the above values.In some embodiments, the drug combination comprises a pharmaceutical composition of an anti-CD40 antibody or an antigen-binding fragment thereof and a pharmaceutical composition of an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the pharmaceutical composition of the anti-CD40 antibody or an antigen-binding fragment thereof is prepared to be suitable for administering a single dose or multiple doses of 30 - 300 mg of the anti-CD40 antibody or an antigen-binding fragment thereof to a patient, and the pharmaceutical composition of the anti-PD-1 antibody or an antigen-binding fragment thereof is prepared to be suitable for administering a single dose or multiple doses of 100 - 200 mg of the anti-PD-1 antibody or an antigen-binding fragment thereof to a patient. In some embodiments, the drug combination comprises a pharmaceutical composition of an anti-CD40 antibody or an antigen-binding fragment thereof and a pharmaceutical composition of an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the pharmaceutical composition of the anti-CD40 antibody or an antigen-binding fragment thereof is prepared to be suitable for administering a single dose or multiple doses of 60 - 200 mg of the anti-CD40 antibody or an antigen-binding fragment thereof to a patient, and the pharmaceutical composition of the anti-PD-1 antibody or an antigen-binding fragment thereof is prepared to be suitable for administering a single dose or multiple doses of 100 - 200 mg of the anti-PD-1 antibody or an antigen-binding fragment thereof to a patient. In some embodiments, the drug combination comprises a pharmaceutical composition of an anti-CD40 antibody or an antigen-binding fragment thereof and a pharmaceutical composition of an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the pharmaceutical composition of the anti-CD40 antibody or an antigen-binding fragment thereof is prepared to be suitable for administering a single dose or multiple doses of 60 mg, 100 mg or 200 mg of the anti-CD40 antibody or an antigen-binding fragment thereof to a patient, and the pharmaceutical composition of the anti-PD-1 antibody or an antigen-binding fragment thereof is prepared to be suitable for administering a single dose or multiple doses of 200 mg of the anti-PD-1 antibody or an antigen-binding fragment thereof to a patient. In some embodiments, the drug combination comprises a pharmaceutical composition of an anti-CD40 antibody or an antigen-binding fragment thereof and a pharmaceutical composition of an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the pharmaceutical composition of the anti-CD40 antibody or an antigen-binding fragment thereof is prepared to be suitable for administering a single dose or multiple doses of 60 mg of the anti-CD40 antibody or an antigen-binding fragment thereof to a patient, and the pharmaceutical composition of the anti-PD-1 antibody or an antigen-binding fragment thereof is prepared to be suitable for administering a single dose or multiple doses of 200 mg of the anti-PD-1 antibody or an antigen-binding fragment thereof to a patient. In some embodiments, the drug combination comprises a pharmaceutical composition of an anti-CD40 antibody or an antigen-binding fragment thereof and a pharmaceutical composition of an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the pharmaceutical composition of the anti-CD40 antibody or an antigen-binding fragment thereof is prepared to be suitable for administering a single dose or multiple doses of 100 mg of the anti-CD40 antibody or an antigen-binding fragment thereof to a patient, and the pharmaceutical composition of the anti-PD-1 antibody or an antigen-binding fragment thereof is prepared to be suitable for administering a single dose or multiple doses of 200 mg of the anti-PD-1 antibody or an antigen-binding fragment thereof to a patient.In some embodiments, the drug combination comprises a pharmaceutical composition of an anti-CD40 antibody or an antigen-binding fragment thereof and a pharmaceutical composition of an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the pharmaceutical composition of the anti-CD40 antibody or an antigen-binding fragment thereof is prepared to be suitable for administering a single dose or multiple doses of 200 mg of the anti-CD40 antibody or an antigen-binding fragment thereof to a patient, and the pharmaceutical composition of the anti-PD-1 antibody or an antigen-binding fragment thereof is prepared to be suitable for administering a single dose or multiple doses of 200 mg of the anti-PD-1 antibody or an antigen-binding fragment thereof to a patient.

[0038] In another aspect, the present application provides a kit for treating a tumor, the kit comprising an anti-CD40 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof, and instructions for using the anti-CD40 antibody or an antigen-binding fragment thereof and the anti-PD-1 antibody or an antigen-binding fragment thereof in combination to treat a tumor.

[0039] In another aspect, the present application provides a kit for treating a tumor, the kit comprising a pharmaceutical composition of an anti-CD40 antibody or an antigen-binding fragment thereof and a pharmaceutical composition of an anti-PD-1 antibody or an antigen-binding fragment thereof, and instructions for using the pharmaceutical composition of the anti-CD40 antibody or an antigen-binding fragment thereof and the pharmaceutical composition of the anti-PD-1 antibody or an antigen-binding fragment thereof in combination to treat a tumor.

[0040] In some embodiments, the pharmaceutical composition of the anti-CD40 antibody or an antigen-binding fragment thereof is a liquid preparation or a solid preparation. In some specific embodiments, the pharmaceutical composition of the anti-CD40 antibody or an antigen-binding fragment thereof is an injection solution. In some specific embodiments, the pharmaceutical composition of the anti-CD40 antibody or an antigen-binding fragment thereof is a freeze-dried preparation. In some embodiments, the pharmaceutical composition of the anti-PD-1 antibody or an antigen-binding fragment thereof is a liquid preparation or a solid preparation. In some specific embodiments, the pharmaceutical composition of the anti-PD-1 antibody or an antigen-binding fragment thereof is an injection solution. In some specific embodiments, the pharmaceutical composition of the anti-PD-1 antibody or an antigen-binding fragment thereof is a freeze-dried preparation.

[0041] In some embodiments, the tumor is a solid tumor. In some specific embodiments, the tumor is a soft tissue sarcoma. In some specific embodiments, the tumor is melanoma.

[0042] Anti-CD40 antibody or its antigen-binding fragment and chemotherapeutic drug

[0043] In one aspect, the present application provides a drug combination comprising an anti-CD40 antibody or an antigen-binding fragment thereof and a chemotherapeutic agent (e.g., anthracycline). In some embodiments, the anthracycline includes, but is not limited to: doxorubicin, epirubicin, pirarubicin, amrubicin, aclarubicin, idarubicin, daunorubicin, mitoxantrone, idamycin, valrubicin, zorubicin, pixantrone, or any combination of the foregoing. In some specific embodiments, the anthracycline includes doxorubicin, epirubicin, mitoxantrone, and daunorubicin. In some specific embodiments, the anthracycline includes doxorubicin. In some specific embodiments, the doxorubicin includes liposomal doxorubicin.

[0044] The present application provides a drug combination comprising an anti-CD40 antibody or an antigen-binding fragment thereof and doxorubicin.

[0045] In some embodiments, the drug combination is packaged in the same kit, and the kit further includes instructions for using the anti-CD40 antibody or an antigen-binding fragment thereof and doxorubicin in combination to treat tumors. In other embodiments, the anti-CD40 antibody or an antigen-binding fragment thereof and doxorubicin in the drug combination are separately packaged in respective cartridges, and the cartridges further include instructions for using the anti-CD40 antibody or an antigen-binding fragment thereof and doxorubicin in combination to treat tumors.

[0046] In some embodiments, the drug combination comprises 10 - 800 mg, 20 - 500 mg, 30 - 300 mg, or 60 - 200 mg of an anti - CD40 antibody or an antigen - binding fragment thereof. In some embodiments, the drug combination comprises 10 mg, 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg, 620 mg, 640 mg, 660 mg, 680 mg, 700 mg, 720 mg, 740 mg, 760 mg, 780 mg, or 800 mg, or an anti - CD40 antibody or an antigen - binding fragment thereof within the range formed by any of the above values. In some embodiments, the drug combination comprises 30 - 300 mg of an anti - CD40 antibody or an antigen - binding fragment thereof. In some embodiments, the drug combination comprises 60 - 200 mg of an anti - CD40 antibody or an antigen - binding fragment thereof. In some embodiments, the drug combination comprises 60 mg, 100 mg, 120 mg, 180 mg, 200 mg, 240 mg, or 300 mg of an anti - CD40 antibody or an antigen - binding fragment thereof. In some embodiments, the drug combination comprises 60 mg, 100 mg, or 200 mg of an anti - CD40 antibody or an antigen - binding fragment thereof. In some embodiments, the drug combination comprises 60 mg of an anti - CD40 antibody or an antigen - binding fragment thereof. In some embodiments, the drug combination comprises 100 mg of an anti - CD40 antibody or an antigen - binding fragment thereof. In some specific embodiments, the drug combination comprises 200 mg of an anti - CD40 antibody or an antigen - binding fragment thereof.

[0047] In some embodiments, the drug combination comprises doxorubicin at a dose of 25 - 150 mg / m 2 、35 - 135 mg / m 2 、50 - 90 mg / m 2 、or 50 - 75 mg / m 2 In some embodiments, the drug combination comprises doxorubicin at a dose of 25 mg / m 2 、35 mg / m 2 、50 mg / m 2 、60 mg / m 2 、75 mg / m 2 、80 mg / m 2 、90 mg / m 2 、100 mg / m2 、 120 mg / m 2 、 135 mg / m 2 or 150 mg / m 2 、 or doxorubicin in the range formed by any of the above values. In some embodiments, the drug combination comprises doxorubicin at a dose of 35 mg / m 2 、 50 mg / m 2 、 75 mg / m 2 、 100 mg / m 2 or 135 mg / m 2 of doxorubicin. In some specific embodiments, the drug combination comprises doxorubicin at a dose of 75 mg / m 2 .

[0048] In some embodiments, the drug combination comprises 10 - 800 mg, 20 - 500 mg, 30 - 300 mg or 60 - 200 mg of an anti - CD40 antibody or an antigen - binding fragment thereof, and 25 - 150 mg / m 2 、 35 - 135 mg / m 2 、 50 - 90 mg / m 2 、 or 50 - 75 mg / m 2 of doxorubicin. In some embodiments, the drug combination comprises 10 mg, 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg,

[0049] 620 mg, 640 mg, 660 mg, 680 mg, 700 mg, 720 mg, 740 mg, 760 mg, 780 mg or 800 mg, or an anti - CD40 antibody or an antigen - binding fragment thereof in the range formed by any of the above values, and 25 mg / m 2 、 35 mg / m 2 、 50 mg / m 2 、 60 mg / m 2 、 75 mg / m 2 、 80 mg / m 2 、 90 mg / m 2 、 100 mg / m 2 、 120 mg / m 2 、 135 mg / m 2 or 150 mg / m 2, or doxorubicin in a range formed by any of the above values. In some embodiments, the drug combination comprises 30 - 300 mg of an anti-CD40 antibody or an antigen-binding fragment thereof, and 50 - 75 mg / m 2 of doxorubicin. In some embodiments, the drug combination comprises 60 - 200 mg of an anti-CD40 antibody or an antigen-binding fragment thereof, and 50 - 75 mg / m 2 of doxorubicin. In some embodiments, the drug combination comprises 60 mg, 100 mg, or 200 mg of an anti-CD40 antibody or an antigen-binding fragment thereof, and 75 mg / m 2 of doxorubicin. In some embodiments, the drug combination comprises 60 mg of an anti-CD40 antibody or an antigen-binding fragment thereof, and 75 mg / m 2 of doxorubicin. In some embodiments, the drug combination comprises 100 mg of an anti-CD40 antibody or an antigen-binding fragment thereof, and 75 mg / m 2 of doxorubicin. In some embodiments, the drug combination comprises 200 mg of an anti-CD40 antibody or an antigen-binding fragment thereof, and 75 mg / m 2 of doxorubicin.

[0050] In some embodiments, in the drug combination, the content of the anti-CD40 antibody or an antigen-binding fragment thereof is a daily dose. In some embodiments, in the drug combination, the content of the anti-CD40 antibody or an antigen-binding fragment thereof is a once-daily dose.

[0051] In some embodiments, in the drug combination, the content of the anti-CD40 antibody or an antigen-binding fragment thereof is a uniform dose.

[0052] In some embodiments, in the drug combination, the content of the anti-CD40 antibody or an antigen-binding fragment thereof is a dose for one treatment cycle, and each treatment cycle is 3 weeks.

[0053] In some embodiments, in the drug combination, the content of doxorubicin is a daily dose. In some embodiments, in the drug combination, the content of doxorubicin is a once-daily dose.

[0054] In some embodiments, in the drug combination, the content of doxorubicin is a dose for one treatment cycle, and each treatment cycle is 3 weeks.

[0055] In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle and comprises 10 - 800 mg, 20 - 500 mg, 30 - 300 mg, or 60 - 200 mg of an anti - CD40 antibody or an antigen - binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle and comprises 10 mg, 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg, 620 mg, 640 mg, 660 mg, 680 mg, 700 mg, 720 mg, 740 mg, 760 mg, 780 mg, or 800 mg, or an anti - CD40 antibody or an antigen - binding fragment thereof within the range formed by any of the above values. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle and comprises 30 - 300 mg of an anti - CD40 antibody or an antigen - binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle and comprises 60 - 200 mg of an anti - CD40 antibody or an antigen - binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle and comprises 60 mg, 100 mg, 120 mg, 180 mg, 200 mg, 240 mg, or 300 mg of an anti - CD40 antibody or an antigen - binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle and comprises 60 mg, 100 mg, or 200 mg of an anti - CD40 antibody or an antigen - binding fragment thereof. In some specific embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle and comprises 60 mg of an anti - CD40 antibody or an antigen - binding fragment thereof. In some specific embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle and comprises 100 mg of an anti - CD40 antibody or an antigen - binding fragment thereof. In some specific embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle and comprises 200 mg of an anti - CD40 antibody or an antigen - binding fragment thereof.

[0056] In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle and comprises a dose of 25 - 150 mg / m 2 、35 - 135 mg / m 2 、50 - 90 mg / m 2 、or 50 - 75 mg / m 2Doxorubicin. In some embodiments, the drug combination is suitable for administration within a single treatment cycle and includes a dose of 25 mg / m 2 、35 mg / m 2 、50 mg / m 2 、60 mg / m 2 、75 mg / m 2 、80 mg / m 2 、90 mg / m 2 、100 mg / m 2 、120 mg / m 2 、135 mg / m 2 or 150 mg / m 2 、or doxorubicin in the range formed by any of the above values. In some embodiments, the drug combination is suitable for administration within a single treatment cycle and includes a dose of 35 mg / m 2 、50 mg / m 2 、75 mg / m 2 、100 mg / m 2 or 135 mg / m 2 of doxorubicin. In some specific embodiments, the drug combination is suitable for administration within a single treatment cycle and includes a dose of 75 mg / m 2 of doxorubicin.

[0057] In some embodiments, the drug combination is suitable for administration within a single treatment cycle and includes 10 - 800 mg, 20 - 500 mg, 30 - 300 mg or 60 - 200 mg of an anti - CD40 antibody or its antigen - binding fragment, and 25 - 150 mg / m 2 、35 - 135 mg / m 2 、50 - 90 mg / m 2 、or 50 - 75 mg / m 2of doxorubicin. In some embodiments, the drug combination is suitable for administration in a single treatment cycle and includes 10 mg, 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg, 620 mg, 640 mg, 660 mg, 680 mg, 700 mg, 720 mg, 740 mg, 760 mg, 780 mg or 800 mg of an anti-CD40 antibody or antigen-binding fragment thereof, and 25 mg / m 2 , 35mg / m 2 , 50mg / m 2 , 60mg / m 2 , 75mg / m 2 , 80mg / m 2 , 90mg / m 2 , 100mg / m 2 , 120mg / m 2 , 135mg / m 2 or 150 mg / m 2 , or doxorubicin in a range formed by any of the above values. In some embodiments, the drug combination is suitable for administration in a single treatment cycle, comprising 30-300 mg of an anti-CD40 antibody or an antigen-binding fragment thereof, and 50-75 mg / m 2 In some embodiments, the drug combination is suitable for administration in a single treatment cycle and comprises 60-200 mg of an anti-CD40 antibody or antigen-binding fragment thereof and 50-75 mg / m 2 In some embodiments, the drug combination is suitable for administration in a single treatment cycle and comprises 60 mg, 100 mg or 200 mg of an anti-CD40 antibody or antigen-binding fragment thereof, and 75 mg / m 2 In some embodiments, the drug set is suitable for administration in a single treatment cycle, which includes 60 mg of an anti-CD40 antibody or an antigen-binding fragment thereof, and 75 mg / m 2 In some embodiments, the drug combination is suitable for administration in a single treatment cycle and comprises 100 mg of an anti-CD40 antibody or antigen-binding fragment thereof and 75 mg / m 2Doxorubicin. In some embodiments, the drug combination is suitable for administration within a single treatment cycle and comprises 200 mg of an anti-CD40 antibody or an antigen-binding fragment thereof, and 75 mg / m 2 of doxorubicin.

[0058] In some embodiments, the drug combination comprises a pharmaceutical composition of an anti-CD40 antibody or an antigen-binding fragment thereof and a pharmaceutical composition of doxorubicin, wherein the pharmaceutical composition of the anti-CD40 antibody or an antigen-binding fragment thereof is prepared to be suitable for administering a single dose or multiple doses of 10 - 800 mg, 20 - 500 mg, 30 - 300 mg, or 60 - 200 mg of the anti-CD40 antibody or an antigen-binding fragment thereof to a patient, and the pharmaceutical composition of doxorubicin is prepared to be suitable for administering a single dose or multiple doses of 25 - 150 mg / m 2 ², 35 - 135 mg / m 2 ², 50 - 90 mg / m 2 ², or 50 - 75 mg / m 2 ² of doxorubicin to a patient. In some embodiments, the drug combination comprises a pharmaceutical composition of an anti-CD40 antibody or an antigen-binding fragment thereof and a pharmaceutical composition of doxorubicin, wherein the pharmaceutical composition of the anti-CD40 antibody or an antigen-binding fragment thereof is prepared to be suitable for administering a single dose or multiple doses of 10 mg, 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg, 620 mg, 640 mg, 660 mg, 680 mg, 700 mg, 720 mg, 740 mg, 760 mg, 780 mg, or 800 mg, or a single dose or multiple doses of the anti-CD40 antibody or an antigen-binding fragment thereof within the range formed by any of the above values to a patient, and the pharmaceutical composition of doxorubicin is prepared to be suitable for administering a single dose or multiple doses of 25 mg / m 2 ², 35 mg / m 2 ², 50 mg / m 2 ², 60 mg / m 2 ², 75 mg / m 2 ², 80 mg / m 2 ², 90 mg / m 2 ², 100 mg / m 2 ², 120 mg / m 2 ², 135 mg / m 2 ² or 150 mg / m 2, or a single or multiple doses of doxorubicin in the range formed by any of the above values. In some embodiments, the drug combination comprises a pharmaceutical composition of an anti-CD40 antibody or an antigen-binding fragment thereof and a pharmaceutical composition of doxorubicin, wherein the pharmaceutical composition of the anti-CD40 antibody or an antigen-binding fragment thereof is prepared to be suitable for administering a single or multiple doses of 30 - 300 mg of the anti-CD40 antibody or an antigen-binding fragment thereof to a patient, and the pharmaceutical composition of doxorubicin is prepared to be suitable for administering a single or multiple doses of 50 - 75 mg / m 2 of doxorubicin to a patient. In some embodiments, the drug combination comprises a pharmaceutical composition of an anti-CD40 antibody or an antigen-binding fragment thereof and a pharmaceutical composition of doxorubicin, wherein the pharmaceutical composition of the anti-CD40 antibody or an antigen-binding fragment thereof is prepared to be suitable for administering a single or multiple doses of 60 - 200 mg of the anti-CD40 antibody or an antigen-binding fragment thereof to a patient, and the pharmaceutical composition of doxorubicin is prepared to be suitable for administering a single or multiple doses of 50 - 75 mg / m 2 of doxorubicin to a patient. In some embodiments, the drug combination comprises a pharmaceutical composition of an anti-CD40 antibody or an antigen-binding fragment thereof and a pharmaceutical composition of doxorubicin, wherein the pharmaceutical composition of the anti-CD40 antibody or an antigen-binding fragment thereof is prepared to be suitable for administering a single or multiple doses of 60 mg, 100 mg or 200 mg of the anti-CD40 antibody or an antigen-binding fragment thereof to a patient, and the pharmaceutical composition of doxorubicin is prepared to be suitable for administering a single or multiple doses of 75 mg / m 2 of doxorubicin to a patient. In some embodiments, the drug combination comprises a pharmaceutical composition of an anti-CD40 antibody or an antigen-binding fragment thereof and a pharmaceutical composition of doxorubicin, wherein the pharmaceutical composition of the anti-CD40 antibody or an antigen-binding fragment thereof is prepared to be suitable for administering a single or multiple doses of 60 mg of the anti-CD40 antibody or an antigen-binding fragment thereof to a patient, and the pharmaceutical composition of doxorubicin is prepared to be suitable for administering a single or multiple doses of 75 mg / m 2 of doxorubicin to a patient. In some embodiments, the drug combination comprises a pharmaceutical composition of an anti-CD40 antibody or an antigen-binding fragment thereof and a pharmaceutical composition of doxorubicin, wherein the pharmaceutical composition of the anti-CD40 antibody or an antigen-binding fragment thereof is prepared to be suitable for administering a single or multiple doses of 100 mg of the anti-CD40 antibody or an antigen-binding fragment thereof to a patient, and the pharmaceutical composition of doxorubicin is prepared to be suitable for administering a single or multiple doses of 75 mg / m 2A single dose or multiple doses of doxorubicin. In some embodiments, the drug combination comprises a pharmaceutical composition of an anti-CD40 antibody or an antigen-binding fragment thereof and a pharmaceutical composition of doxorubicin, wherein the pharmaceutical composition of the anti-CD40 antibody or an antigen-binding fragment thereof is prepared to be suitable for administering a single dose or multiple doses of 200 mg of the anti-CD40 antibody or an antigen-binding fragment thereof to a patient, and the pharmaceutical composition of doxorubicin is prepared to be suitable for administering 75 mg / m 2 A single dose or multiple doses of doxorubicin.

[0059] In another aspect, the present application provides a kit for treating tumors, the kit comprising an anti-CD40 antibody or an antigen-binding fragment thereof and doxorubicin, as well as instructions for using the anti-CD40 antibody or an antigen-binding fragment thereof and doxorubicin in combination to treat tumors.

[0060] In another aspect, the present application provides a kit for treating tumors, the kit comprising a pharmaceutical composition of an anti-CD40 antibody or an antigen-binding fragment thereof and a pharmaceutical composition of doxorubicin, as well as instructions for using the pharmaceutical composition of the anti-CD40 antibody or an antigen-binding fragment thereof and the pharmaceutical composition of doxorubicin in combination to treat tumors.

[0061] In some embodiments, the pharmaceutical composition of the anti-CD40 antibody or an antigen-binding fragment thereof is a liquid preparation or a solid preparation. In some specific embodiments, the pharmaceutical composition of the anti-CD40 antibody or an antigen-binding fragment thereof is an injection. In some specific embodiments, the pharmaceutical composition of the anti-CD40 antibody or an antigen-binding fragment thereof is a freeze-dried preparation. In some embodiments, the pharmaceutical composition of doxorubicin is a liquid preparation or a solid preparation. In some specific embodiments, the pharmaceutical composition of doxorubicin is an injection. In some specific embodiments, the pharmaceutical composition of doxorubicin is a suspension. In some specific embodiments, the pharmaceutical composition of doxorubicin is a powder for injection.

[0062] In some specific embodiments, the tumor is a solid tumor. In some specific embodiments, the tumor is a soft tissue sarcoma.

[0063] Treatment regimen

[0064] The present application also provides a method for treating tumors in a subject, which comprises administering to the subject a therapeutically effective amount of the drug combination of the present application. Additionally, the present application also provides the use of the drug combination of the present application in the preparation of a drug for treating tumors in a subject. In some specific embodiments, the present application also provides the use of the drug combination of the present application in the preparation of a drug for treating tumors in a subject at the third line or more advanced lines (e.g., the second line or the first line). Additionally, the present application also provides the use of the drug combination of the present application for treating tumors in a subject.

[0065] In another aspect, the present application also provides a method for treating tumors in a subject, which comprises administering to the subject a therapeutically effective amount of the anti-CD40 antibody or an antigen-binding fragment thereof of the present application and a second therapeutic agent. Additionally, the present application also provides the use of the anti-CD40 antibody or an antigen-binding fragment thereof of the present application and a second therapeutic agent in the preparation of a medicament for treating tumors in a subject. In some specific embodiments, the present application also provides the use of the anti-CD40 antibody or an antigen-binding fragment thereof of the present application and a second therapeutic agent in the preparation of a medicament for treating tumors in a subject at the third-line or more advanced lines (e.g., second-line or first-line). Additionally, the present application also provides the use of the anti-CD40 antibody or an antigen-binding fragment thereof of the present application and a second therapeutic agent for treating tumors in a subject. Additionally, the present application also provides the use of the anti-CD40 antibody or an antigen-binding fragment thereof of the present application in the preparation of a medicament for combination use with a second therapeutic agent for treating tumors.

[0066] In some specific embodiments, the present application also provides a method for treating tumors in a subject, which comprises administering to the subject a therapeutically effective amount of the anti-CD40 antibody or an antigen-binding fragment thereof of the present application and an anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., penpulimab). In some specific embodiments, the present application also provides a method for treating tumors in a subject, which comprises administering to the subject a therapeutically effective amount of the anti-CD40 antibody or an antigen-binding fragment thereof of the present application and a chemotherapeutic drug (e.g., anthracyclines). In some specific embodiments, the present application also provides a method for treating tumors in a subject, which comprises administering to the subject a therapeutically effective amount of the anti-CD40 antibody or an antigen-binding fragment thereof of the present application and anthracyclines (e.g., doxorubicin).

[0067] In some specific embodiments, the present application provides the use of the anti-CD40 antibody or its antigen-binding fragment of the present application and the anti-PD-1 antibody or its antigen-binding fragment (e.g., penpulimab) in the preparation of a medicament for treating tumors in a subject. In some specific embodiments, the present application provides the use of the anti-CD40 antibody or its antigen-binding fragment of the present application and a chemotherapeutic drug (e.g., anthracyclines) in the preparation of a medicament for treating tumors in a subject. In some specific embodiments, the present application provides the use of the anti-CD40 antibody or its antigen-binding fragment of the present application and anthracyclines (e.g., doxorubicin) in the preparation of a medicament for treating tumors in a subject. In some specific embodiments, the present application further provides the use of the anti-CD40 antibody or its antigen-binding fragment of the present application and the anti-PD-1 antibody or its antigen-binding fragment (e.g., penpulimab) in the preparation of a medicament for treating tumors in a subject at the third or more frontlines (e.g., the second or first line). In some specific embodiments, the present application further provides the use of the anti-CD40 antibody or its antigen-binding fragment of the present application and a chemotherapeutic drug (e.g., anthracyclines) in the preparation of a medicament for treating tumors in a subject at the third or more frontlines (e.g., the second or first line). In some specific embodiments, the present application further provides the use of the anti-CD40 antibody or its antigen-binding fragment of the present application and anthracyclines (e.g., doxorubicin) in the preparation of a medicament for treating tumors in a subject at the third or more frontlines (e.g., the second or first line).

[0068] In some specific embodiments, the present application further provides the use of the anti-CD40 antibody or its antigen-binding fragment of the present application and the anti-PD-1 antibody or its antigen-binding fragment (e.g., penpulimab) in treating tumors in a subject. In some specific embodiments, the present application further provides the use of the anti-CD40 antibody or its antigen-binding fragment of the present application and a chemotherapeutic drug (e.g., anthracyclines) in treating tumors in a subject. In some specific embodiments, the present application further provides the use of the anti-CD40 antibody or its antigen-binding fragment of the present application and anthracyclines (e.g., doxorubicin) in treating tumors in a subject.

[0069] In some specific embodiments, the present application further provides the use of the anti-CD40 antibody or its antigen-binding fragment of the present application in the preparation of a medicament for combined use with the anti-PD-1 antibody or its antigen-binding fragment (e.g., penpulimab) in treating tumors. In some specific embodiments, the present application further provides the use of the anti-CD40 antibody or its antigen-binding fragment of the present application in the preparation of a medicament for combined use with a chemotherapeutic drug (e.g., anthracyclines) in treating tumors. In some specific embodiments, the present application further provides the use of the anti-CD40 antibody or its antigen-binding fragment of the present application in the preparation of a medicament for combined use with anthracyclines (e.g., doxorubicin) in treating tumors.

[0070] On the other hand, the present application also provides the use of the anti-CD40 antibody or antigen-binding fragment thereof of the present application in the preparation of a medicament for treating a tumor of a subject, wherein the medicament is for use in combination with a second therapeutic agent of the present application. In some specific embodiments, the present application also provides the use of the anti-CD40 antibody or antigen-binding fragment thereof of the present application in the preparation of a medicament for treating a tumor of a subject, wherein the medicament is for use in combination with an anti-PD-1 antibody or antigen-binding fragment thereof (e.g., penpulimab) of the present application. In some specific embodiments, the present application also provides the use of the anti-CD40 antibody or antigen-binding fragment thereof of the present application in the preparation of a medicament for treating a tumor of a subject, wherein the medicament is for use in combination with a chemotherapeutic drug (e.g., anthracyclines). In some specific embodiments, the present application also provides the use of the anti-CD40 antibody or antigen-binding fragment thereof of the present application in the preparation of a medicament for treating a tumor of a subject, wherein the medicament is for use in combination with anthracyclines (e.g., doxorubicin).

[0071] In some specific embodiments, the present application also provides the use of the anti-CD40 antibody or antigen-binding fragment thereof of the present application in the preparation of a medicament for treating a tumor of a subject at the third line or more advanced lines (e.g., the second line or the first line), wherein the medicament is for use in combination with a second therapeutic agent of the present application. In some specific embodiments, the present application also provides the use of the anti-CD40 antibody or antigen-binding fragment thereof of the present application in the preparation of a medicament for treating a tumor of a subject at the third line or more advanced lines (e.g., the second line or the first line), wherein the medicament is for use in combination with an anti-PD-1 antibody or antigen-binding fragment thereof (e.g., penpulimab) of the present application. In some specific embodiments, the present application also provides the use of the anti-CD40 antibody or antigen-binding fragment thereof of the present application in the preparation of a medicament for treating a tumor of a subject at the third line or more advanced lines (e.g., the second line or the first line), wherein the medicament is for use in combination with a chemotherapeutic drug (e.g., anthracyclines). In some specific embodiments, the present application also provides the use of the anti-CD40 antibody or antigen-binding fragment thereof of the present application in the preparation of a medicament for treating a tumor of a subject at the third line or more advanced lines (e.g., the second line or the first line), wherein the medicament is for use in combination with anthracyclines (e.g., doxorubicin).

[0072] In some embodiments, in the use or method, the anti-CD40 antibody or its antigen-binding fragment and the second therapeutic agent can be administered simultaneously, sequentially, and / or alternately. In some embodiments, in the use or method, the anti-CD40 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment (e.g., penpulimab) can be administered simultaneously, sequentially, and / or alternately. In some embodiments, in the use or method, the anti-CD40 antibody or its antigen-binding fragment and a chemotherapeutic drug (e.g., anthracyclines) can be administered simultaneously, sequentially, and / or alternately. In some embodiments, in the use or method, the anti-CD40 antibody or its antigen-binding fragment and anthracyclines (e.g., doxorubicin) can be administered simultaneously, sequentially, and / or alternately.

[0073] In some embodiments, in the use or method, the anti-CD40 antibody or its antigen-binding fragment and the second therapeutic agent are each in the form of a pharmaceutical composition and can be administered simultaneously, sequentially, and / or alternately. In some embodiments, in the use or method, the anti-CD40 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment (e.g., penpulimab) are each in the form of a pharmaceutical composition and can be administered simultaneously, sequentially, and / or alternately. In some specific embodiments, in the use or method, the anti-CD40 antibody or its antigen-binding fragment and a chemotherapeutic drug (e.g., anthracyclines) are each in the form of a pharmaceutical composition and can be administered simultaneously, sequentially, and / or alternately. In some specific embodiments, in the use or method, the anti-CD40 antibody or its antigen-binding fragment and anthracyclines (e.g., doxorubicin) are each in the form of a pharmaceutical composition and can be administered simultaneously, sequentially, and / or alternately.

[0074] In some embodiments, in the use or method, the anti-CD40 antibody or its antigen-binding fragment and the second therapeutic agent are administered according to the same or different dosing regimens. In some embodiments, in the use or method, the anti-CD40 antibody or its antigen-binding fragment and the second therapeutic agent are administered according to different dosing regimens.

[0075] In some embodiments, in the use or method, the anti-CD40 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment (e.g., penpulimab) are administered according to the same or different dosing regimens. In some embodiments, in the use or method, the anti-CD40 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment (e.g., penpulimab) are administered according to different dosing regimens.

[0076] In some embodiments, in the use or method, the anti-CD40 antibody or its antigen-binding fragment and the chemotherapeutic agent (e.g., anthracycline) are administered according to the same or different dosing regimens. In some embodiments, in the use or method, the anti-CD40 antibody or its antigen-binding fragment and the anthracycline (e.g., doxorubicin) are administered according to the same or different dosing regimens. In some embodiments, in the use or method, the anti-CD40 antibody or its antigen-binding fragment and the anthracycline (e.g., doxorubicin) are administered according to different dosing regimens.

[0077] In some embodiments, in the use or method, the anti-CD40 antibody or its antigen-binding fragment is administered once a week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, in the use or method, the anti-CD40 antibody or its antigen-binding fragment is administered once a week (±3 days), once every two weeks (±3 days), once every three weeks (±3 days), or once every four weeks (±3 days). In a specific embodiment, in the use or method, the anti-CD40 antibody or its antigen-binding fragment is administered once every three weeks (±3 days). In some specific embodiments, in the use or method, the anti-CD40 antibody or its antigen-binding fragment is administered at a dose of 10 - 800 mg, 20 - 500 mg, 30 - 300 mg, or 60 - 200 mg each time. In some specific embodiments, in the use or method, the anti-CD40 antibody or its antigen-binding fragment is administered at a dose of 10 mg, 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg, 620 mg, 640 mg, 660 mg, 680 mg, 700 mg, 720 mg, 740 mg, 760 mg, 780 mg, or 800 mg, or a dose within the range formed by any of the above values each time. In some specific embodiments, in the use or method, the anti-CD40 antibody or its antigen-binding fragment is administered at a dose of 30 - 300 mg each time. In some specific embodiments, in the use or method, the anti-CD40 antibody or its antigen-binding fragment is administered at a dose of 60 - 200 mg each time. In some specific embodiments, in the use or method, the anti-CD40 antibody or its antigen-binding fragment is administered at a dose of 60 mg, 100 mg, 120 mg, 180 mg, 200 mg, 240 mg, or 300 mg each time. In some specific embodiments, in the use or method, the anti-CD40 antibody or its antigen-binding fragment is administered at a dose of 60 mg, 100 mg, or 200 mg each time. In some specific embodiments, in the use or method, the anti-CD40 antibody or its antigen-binding fragment is administered at a dose of 60 mg each time. In some specific embodiments, in the use or method, the anti-CD40 antibody or its antigen-binding fragment is administered at a dose of 100 mg each time. In some specific embodiments, in the use or method, the anti-CD40 antibody or its antigen-binding fragment is administered at a dose of 200 mg each time.

[0078] In some specific embodiments, in the described use or method, the anti-CD40 antibody or its antigen-binding fragment is administered once a week, once every two weeks, once every three weeks, or once every four weeks, each time at a dose of 10 - 800 mg, 20 - 500 mg, 30 - 300 mg, or 60 - 200 mg. In some specific embodiments, in the described use or method, the anti-CD40 antibody or its antigen-binding fragment is administered once every three weeks, each time at a dose of 10 - 800 mg, 20 - 500 mg, 30 - 300 mg, or 60 - 200 mg. In some specific embodiments, in the described use or method, the anti-CD40 antibody or its antigen-binding fragment is administered once every three weeks, each time at a dose of 10 mg, 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg, 620 mg, 640 mg, 660 mg, 680 mg, 700 mg, 720 mg, 740 mg, 760 mg, 780 mg, or 800 mg, or a dose within the range formed by any of the above values. In some specific embodiments, in the described use or method, the anti-CD40 antibody or its antigen-binding fragment is administered once every three weeks, each time at a dose of 30 - 300 mg. In some specific embodiments, in the described use or method, the anti-CD40 antibody or its antigen-binding fragment is administered once every three weeks, each time at a dose of 60 - 200 mg. In some specific embodiments, in the described use or method, the anti-CD40 antibody or its antigen-binding fragment is administered once every three weeks, each time at a dose of 60 mg, 100 mg, 120 mg, 180 mg, 200 mg, 240 mg, or 300 mg. In some specific embodiments, in the described use or method, the anti-CD40 antibody or its antigen-binding fragment is administered once every three weeks, each time at a dose of 60 mg, 100 mg, or 200 mg. In some specific embodiments, in the described use or method, the anti-CD40 antibody or its antigen-binding fragment is administered once every three weeks, each time at a dose of 60 mg. In some specific embodiments, in the described use or method, the anti-CD40 antibody or its antigen-binding fragment is administered once every three weeks, each time at a dose of 100 mg. In some specific embodiments, in the described use or method, the anti-CD40 antibody or its antigen-binding fragment is administered once every three weeks, each time at a dose of 200 mg.

[0079] In some specific embodiments, in the use or method, the anti-CD40 antibody or its antigen-binding fragment is administered at a dose of 0.01-40 mg / kg, 0.01-30 mg / kg, 0.01-20 mg / kg, 0.01-10 mg / kg, 0.01-5 mg / kg, 0.01-3 mg / kg, 0.1-40 mg / kg, 0.1-30 mg / kg, 0.1-20 mg / kg, 0.1-10 mg / kg, 0.1-5 mg / kg, 0.1-3 mg / kg, 0.3-40 mg / kg, 0.3-30 mg / kg, 0.3-20 mg / kg, 0.3-10 mg / kg, 0.3-5 mg / kg, 0.3-3 mg / kg, 0.5-40 mg / kg, 0.5-30 mg / kg, 0.5-20 mg / kg, 0.5-10 mg / kg, 0.5-5 mg / kg, 0.5-3 mg / kg, 1-40 mg / kg, 1-30 mg / kg, 1-20 mg / kg, 1-10 mg / kg, 1-5 mg / kg, 1-3 mg / kg, 3-40 mg / kg, 3-30 mg / kg, 3-20 mg / kg, 3-10 mg / kg, 3-5 mg / kg, 1-5 mg / kg, or 1-3 mg / kg each time. In some specific embodiments, in the use or method, the anti-CD40 antibody or its antigen-binding fragment is administered at a dose of 0.01 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.8 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.5 mg / kg, 6 mg / kg, 6.5 mg / kg, 8 mg / kg, 10 mg / kg, 20 mg / kg, 30 mg / kg or 40 mg / kg, or a dose within the range formed by any of the above values each time. In some specific embodiments, in the use or method, the anti-CD40 antibody or its antigen-binding fragment is administered at a dose of 0.3-5 mg / kg, 0.5-5 mg / kg or 0.5-3 mg / kg each time. In some specific embodiments, in the use or method, the anti-CD40 antibody or its antigen-binding fragment is administered at a dose of 0.3 mg / kg, 0.5 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg or 3 mg / kg each time.

[0080] In some specific embodiments, in the described use or method, the anti-CD40 antibody or its antigen-binding fragment is administered once every 3 weeks, each time at a dose of 0.01 - 40 mg / kg, 0.01 - 30 mg / kg, 0.01 - 20 mg / kg, 0.01 - 10 mg / kg, 0.01 - 5 mg / kg, 0.01 - 3 mg / kg, 0.1 - 40 mg / kg, 0.1 - 30 mg / kg, 0.1 - 20 mg / kg, 0.1 - 10 mg / kg, 0.1 - 5 mg / kg, 0.1 - 3 mg / kg, 0.3 - 40 mg / kg, 0.3 - 30 mg / kg, 0.3 - 20 mg / kg, 0.3 - 10 mg / kg, 0.3 - 5 mg / kg, 0.3 - 3 mg / kg, 0.5 - 40 mg / kg, 0.5 - 30 mg / kg, 0.5 - 20 mg / kg, 0.5 - 10 mg / kg, 0.5 - 5 mg / kg, 0.5 - 3 mg / kg, 1 - 40 mg / kg, 1 - 30 mg / kg, 1 - 20 mg / kg, 1 - 10 mg / kg, 1 - 5 mg / kg, 1 - 3 mg / kg, 3 - 40 mg / kg, 3 - 30 mg / kg, 3 - 20 mg / kg, 3 - 10 mg / kg, 3 - 5 mg / kg, 1 - 5 mg / kg, or 1 - 3 mg / kg. In some specific embodiments, in the described use or method, the anti-CD40 antibody or its antigen-binding fragment is administered once every 3 weeks, each time at a dose of 0.01 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.8 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.5 mg / kg, 6 mg / kg, 6.5 mg / kg, 8 mg / kg, 10 mg / kg, 20 mg / kg, 30 mg / kg or 40 mg / kg, or a dose within the range formed by any of the above values. In some specific embodiments, in the described use or method, the anti-CD40 antibody or its antigen-binding fragment is administered once every 3 weeks, each time at a dose of 0.3 - 5 mg / kg, 0.5 - 5 mg / kg or 0.5 - 3 mg / kg. In some specific embodiments, in the described use or method, the anti-CD40 antibody or its antigen-binding fragment is administered once every 3 weeks, each time at a dose of 0.3 mg / kg, 0.5 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg or 3 mg / kg.

[0081] In some embodiments, in the use or method, the anti-PD-1 antibody or its antigen-binding fragment is administered once a week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, in the use or method, the anti-PD-1 antibody or its antigen-binding fragment is administered once a week (±3 days), once every two weeks (±3 days), once every three weeks (±3 days), or once every four weeks (±3 days). In a specific embodiment, in the use or method, the anti-PD-1 antibody or its antigen-binding fragment is administered once every three weeks (±3 days). In some specific embodiments, in the use or method, the anti-PD-1 antibody or its antigen-binding fragment is administered at a dose of 10-800 mg, 50-500 mg, or 100-200 mg each time. In some specific embodiments, in the use or method, the anti-PD-1 antibody or its antigen-binding fragment is administered at a dose of 10 mg, 50 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg or 800 mg, or a dose within the range formed by any of the above values each time. In some specific embodiments, in the use or method, the anti-PD-1 antibody or its antigen-binding fragment is administered at a dose of 100-200 mg each time. In some specific embodiments, in the use or method, the anti-PD-1 antibody or its antigen-binding fragment is administered at a dose of 200 mg each time.

[0082] In some specific embodiments, in the use or method, the anti-PD-1 antibody or its antigen-binding fragment is administered once a week, once every two weeks, once every three weeks, or once every four weeks, each time at a dose of 10 - 800 mg, 50 - 500 mg, or 100 - 200 mg. In some specific embodiments, in the use or method, the anti-PD-1 antibody or its antigen-binding fragment is administered once every three weeks, each time at a dose of 10 - 800 mg, 50 - 500 mg, or 100 - 200 mg. In some specific embodiments, in the use or method, the anti-PD-1 antibody or its antigen-binding fragment is administered once every three weeks, each time at a dose of 10 mg, 50 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg or 800 mg, or a dose within the range formed by any of the above values. In some specific embodiments, in the use or method, the anti-PD-1 antibody or its antigen-binding fragment is administered once every three weeks, each time at a dose of 100 - 200 mg. In some specific embodiments, in the use or method, the anti-PD-1 antibody or its antigen-binding fragment is administered once every three weeks, each time at a dose of 200 mg.

[0083] In some embodiments, in the use or method, the anti-PD-1 antibody or its antigen-binding fragment is administered at a dose of 0.1-50 mg / kg, 0.1-40 mg / kg, 0.1-30 mg / kg, 0.1-20 mg / kg, 0.1-10 mg / kg, 1-50 mg / kg, 1-40 mg / kg, 1-30 mg / kg, 1-20 mg / kg, 1-10 mg / kg, 3-50 mg / kg, 3-40 mg / kg, 3-30 mg / kg, 3-20 mg / kg, 3-10 mg / kg, 1-5 mg / kg, or 3-5 mg / kg each time. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered at a dose of 0.1 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.5 mg / kg, 6 mg / kg, 6.5 mg / kg, 7 mg / kg, 7.5 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 20 mg / kg, 30 mg / kg or 40 mg / kg, 50 mg / kg, or a dose within the range formed by any of the above values each time. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered at a dose of 1-5 mg / kg each time. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered at a dose of 2 mg / kg, 3 mg / kg or 5 mg / kg each time.

[0084] In some embodiments, in the use or method, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 3 weeks, each time at a dose of 0.1-50 mg / kg, 0.1-40 mg / kg, 0.1-30 mg / kg, 0.1-20 mg / kg, 0.1-10 mg / kg, 1-50 mg / kg, 1-40 mg / kg, 1-30 mg / kg, 1-20 mg / kg, 1-10 mg / kg, 3-50 mg / kg, 3-40 mg / kg, 3-30 mg / kg, 3-20 mg / kg, 3-10 mg / kg, 1-5 mg / kg, or 3-5 mg / kg. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 3 weeks, each time at a dose of 0.1 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.5 mg / kg, 6 mg / kg, 6.5 mg / kg, 7 mg / kg, 7.5 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg or 50 mg / kg, or a dose within the range formed by any of the above values. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 3 weeks, each time at a dose of 1-5 mg / kg. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 3 weeks, each time at a dose of 2 mg / kg, 3 mg / kg or 5 mg / kg.

[0085] In some embodiments, in the use or method, the chemotherapeutic drug (e.g., anthracycline) is administered once a week, once every 2 weeks, once every 3 weeks, or once every 4 weeks. In some embodiments, in the use or method, the anthracycline (e.g., doxorubicin) is administered once a week, once every 2 weeks, once every 3 weeks, or once every 4 weeks. In some embodiments, in the use or method, the anthracycline (e.g., doxorubicin) is administered once a week (±3 days), once every 2 weeks (±3 days), once every 3 weeks (±3 days), or once every 4 weeks (±3 days). In a specific embodiment, in the use or method, the anthracycline (e.g., doxorubicin) is administered once every 3 weeks (±3 days). In some specific embodiments, in the use or method, the doxorubicin is administered at a dose of 25-150 mg / m 2 、35-135 mg / m 2 、50-90 mg / m 2 、or 50-75 mg / m 2 each time. In some specific embodiments, in the use or method, the doxorubicin is administered at a dose of 25 mg / m2 , 35 mg / m 2 , 50 mg / m 2 , 60 mg / m 2 , 75 mg / m 2 , 80 mg / m 2 , 90 mg / m 2 , 100 mg / m 2 , 120 mg / m 2 , 135 mg / m 2 or 150 mg / m 2 , or a dose within the range formed by any of the above values is administered. In some specific embodiments, in the said use or method, the doxorubicin is administered at a dose of 35 mg / m 2 , 50 mg / m 2 , 75 mg / m 2 , 100 mg / m 2 or 135 mg / m 2 each time. In some specific embodiments, in the said use or method, the doxorubicin is administered at a dose of 75 mg / m 2 each time.

[0086] In some specific embodiments, in the said use or method, the doxorubicin is administered once a week, once every two weeks, once every three weeks, or once every four weeks, each time at a dose of 25 - 150 mg / m 2 , 35 - 135 mg / m 2 , 50 - 90 mg / m 2 , or 50 - 75 mg / m 2 each time. In some specific embodiments, in the said use or method, the doxorubicin is administered once every three weeks, each time at a dose of 25 - 150 mg / m 2 , 35 - 135 mg / m 2 , 50 - 90 mg / m 2 , or 50 - 75 mg / m 2 each time. In some specific embodiments, in the said use or method, the doxorubicin is administered once every three weeks, each time at a dose of 25 mg / m 2 , 35 mg / m 2 , 50 mg / m 2 , 60 mg / m 2 , 75 mg / m 2 , 80 mg / m 2 , 90 mg / m 2 , 100 mg / m 2 , 120 mg / m 2 , 135 mg / m 2 or 150 mg / m2 administered at a dose within the range formed by the above or any of the above values. In some specific embodiments, in the use or method, doxorubicin is administered once every 3 weeks, each time at a dose of 35 mg / m 2 、50 mg / m 2 、75 mg / m 2 、100 mg / m 2 or 135 mg / m 2 administered at a dose of. In some specific embodiments, in the use or method, doxorubicin is administered once every 3 weeks, each time at a dose of 75 mg / m 2 administered at a dose of.

[0087] In some embodiments, in the use or method, the anti-CD40 antibody or its antigen-binding fragment and the second therapeutic agent have the same or different treatment cycles respectively. In some embodiments, in the use or method, the anti-CD40 antibody or its antigen-binding fragment and the second therapeutic agent have the same treatment cycle, for example, each 1 week (±3 days), each 2 weeks (±3 days), each 3 weeks (±3 days) or each 4 weeks (±3 days) is a treatment cycle. In some specific embodiments, in the use or method, the anti-CD40 antibody or its antigen-binding fragment and the second therapeutic agent have a treatment cycle of each 3 weeks (±3 days).

[0088] In some embodiments, in the above use or method, the anti-CD40 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment (for example, penpulimab) have the same treatment cycle, for example, each 1 week (±3 days), each 2 weeks (±3 days), each 3 weeks (±3 days) or each 4 weeks (±3 days) is a treatment cycle. In some specific embodiments, the anti-CD40 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment (for example, penpulimab) have a treatment cycle of each 3 weeks (±3 days).

[0089] In some embodiments, in the above use or method, the anti-CD40 antibody or its antigen-binding fragment and the chemotherapeutic drug (for example, anthracyclines) have the same treatment cycle, for example, each 1 week (±3 days), each 2 weeks (±3 days), each 3 weeks (±3 days) or each 4 weeks (±3 days) is a treatment cycle. In some embodiments, in the above use or method, the anti-CD40 antibody or its antigen-binding fragment and anthracyclines (for example, doxorubicin) have the same treatment cycle, for example, each 1 week (±3 days), each 2 weeks (±3 days), each 3 weeks (±3 days) or each 4 weeks (±3 days) is a treatment cycle. In a specific embodiment, the anti-CD40 antibody or its antigen-binding fragment and anthracyclines (for example, doxorubicin) have a treatment cycle of each 3 weeks (±3 days).

[0090] In some embodiments, in the above-mentioned method or use, each treatment cycle is 3 weeks, and an anti-CD40 antibody or its antigen-binding fragment and a second therapeutic agent are administered in each treatment cycle. In some specific embodiments, each treatment cycle is 3 weeks, and an anti-CD40 antibody or its antigen-binding fragment and a second therapeutic agent are each administered once in each treatment cycle. In some specific embodiments, each treatment cycle is 3 weeks, an anti-CD40 antibody or its antigen-binding fragment is administered once on the first day of each treatment cycle, and a second therapeutic agent is administered once on the first day of each treatment cycle.

[0091] In some embodiments, in the above-mentioned method or use, each treatment cycle is 3 weeks, and an anti-CD40 antibody or its antigen-binding fragment and an anti-PD-1 antibody or its antigen-binding fragment (e.g., penpulimab) are administered in each treatment cycle. In some specific embodiments, each treatment cycle is 3 weeks, and an anti-CD40 antibody or its antigen-binding fragment and an anti-PD-1 antibody or its antigen-binding fragment (e.g., penpulimab) are each administered once in each treatment cycle. In some specific embodiments, each treatment cycle is 3 weeks, an anti-CD40 antibody or its antigen-binding fragment is administered once on the first day of each treatment cycle, and an anti-PD-1 antibody or its antigen-binding fragment (e.g., penpulimab) is administered once on the first day of each treatment cycle.

[0092] In some embodiments, in the above-mentioned method or use, each treatment cycle is 3 weeks, and an anti-CD40 antibody or its antigen-binding fragment and a chemotherapeutic drug (e.g., anthracyclines) are administered in each treatment cycle. In some embodiments, in the above-mentioned method or use, each treatment cycle is 3 weeks, and an anti-CD40 antibody or its antigen-binding fragment and anthracyclines (e.g., doxorubicin) are administered in each treatment cycle. In some specific embodiments, each treatment cycle is 3 weeks, and an anti-CD40 antibody or its antigen-binding fragment and anthracyclines (e.g., doxorubicin) are each administered once in each treatment cycle. In some specific embodiments, each treatment cycle is 3 weeks, an anti-CD40 antibody or its antigen-binding fragment is administered once on the first day of each treatment cycle, and anthracyclines (e.g., doxorubicin) are administered once on the first day of each treatment cycle.

[0093] In some specific embodiments, in the said use or method, every 3 weeks constitutes a treatment cycle, and within each treatment cycle, 10 - 800 mg, 20 - 500 mg, 30 - 300 mg, or 60 - 200 mg of an anti - CD40 antibody or its antigen - binding fragment is administered, and 10 - 800 mg, 50 - 500 mg, or 100 - 200 mg of an anti - PD - 1 antibody or its antigen - binding fragment is administered. In some specific embodiments, in the said use or method, every 3 weeks constitutes a treatment cycle, and within each treatment cycle, 30 - 300 mg of an anti - CD40 antibody or its antigen - binding fragment is administered, and 100 - 200 mg of an anti - PD - 1 antibody or its antigen - binding fragment is administered. In some specific embodiments, in the said use or method, every 3 weeks constitutes a treatment cycle, and within each treatment cycle, 60 - 200 mg of an anti - CD40 antibody or its antigen - binding fragment is administered, and 100 - 200 mg of an anti - PD - 1 antibody or its antigen - binding fragment is administered. In some specific embodiments, in the said use or method, every 3 weeks constitutes a treatment cycle, and on the first day of each treatment cycle, 30 - 300 mg of an anti - CD40 antibody or its antigen - binding fragment is administered, and on the first day of each treatment cycle, 100 - 200 mg of an anti - PD - 1 antibody or its antigen - binding fragment is administered. In some specific embodiments, in the said use or method, every 3 weeks constitutes a treatment cycle, and on the first day of each treatment cycle, 60 - 200 mg of an anti - CD40 antibody or its antigen - binding fragment is administered, and on the first day of each treatment cycle, 100 - 200 mg of an anti - PD - 1 antibody or its antigen - binding fragment is administered. In some specific embodiments, in the said use or method, every 3 weeks constitutes a treatment cycle, and on the first day of each treatment cycle, 60 mg, 100 mg, or 200 mg of an anti - CD40 antibody or its antigen - binding fragment is administered, and on the first day of each treatment cycle, 200 mg of an anti - PD - 1 antibody or its antigen - binding fragment is administered. In some specific embodiments, in the said use or method, every 3 weeks constitutes a treatment cycle, and on the first day of each treatment cycle, 60 mg of an anti - CD40 antibody or its antigen - binding fragment is administered, and on the first day of each treatment cycle, 200 mg of an anti - PD - 1 antibody or its antigen - binding fragment is administered. In some specific embodiments, in the said use or method, every 3 weeks constitutes a treatment cycle, and on the first day of each treatment cycle, 100 mg of an anti - CD40 antibody or its antigen - binding fragment is administered, and on the first day of each treatment cycle, 200 mg of an anti - PD - 1 antibody or its antigen - binding fragment is administered.

[0094] In some specific embodiments, in the described use or method, every 3 weeks is a treatment cycle, and 10 - 800 mg, 20 - 500 mg, 30 - 300 mg, or 60 - 200 mg of an anti - CD40 antibody or its antigen - binding fragment is administered in each treatment cycle, and 25 - 150 mg / m 2 、35 - 135 mg / m 2 、50 - 90 mg / m 2 、or 50 - 75 mg / m 2 of doxorubicin. In some specific embodiments, in the described use or method, every 3 weeks is a treatment cycle, and 30 - 300 mg of an anti - CD40 antibody or its antigen - binding fragment is administered in each treatment cycle, and 35 mg / m 2 、50 mg / m 2 、75 mg / m 2 、100 mg / m 2 or 135 mg / m 2 of doxorubicin. In some specific embodiments, in the described use or method, every 3 weeks is a treatment cycle, and 60 - 200 mg of an anti - CD40 antibody or its antigen - binding fragment is administered in each treatment cycle, and 35 mg / m 2 、50 mg / m 2 、75 mg / m 2 、100 mg / m 2 or 135 mg / m 2 of doxorubicin. In some specific embodiments, in the described use or method, every 3 weeks is a treatment cycle, and 30 - 300 mg of an anti - CD40 antibody or its antigen - binding fragment is administered on the first day of each treatment cycle, and 35 mg / m 2 、50 mg / m 2 、75 mg / m 2 、100 mg / m 2 or 135 mg / m 2 of doxorubicin. In some specific embodiments, in the described use or method, every 3 weeks is a treatment cycle, and 60 - 200 mg of an anti - CD40 antibody or its antigen - binding fragment is administered on the first day of each treatment cycle, and 35 mg / m 2 、50 mg / m 2 、75 mg / m 2 、100 mg / m 2 or 135 mg / m 2Doxorubicin. In some specific embodiments, in the said use or method, every 3 weeks is a treatment cycle, and on the first day of each treatment cycle, 60 mg, 100 mg or 200 mg of an anti-CD40 antibody or its antigen-binding fragment is administered, and 75 mg / m is administered on the first day of each treatment cycle 2 Doxorubicin. In some specific embodiments, in the said use or method, every 3 weeks is a treatment cycle, and on the first day of each treatment cycle, 60 mg of an anti-CD40 antibody or its antigen-binding fragment is administered, and 75 mg / m is administered on the first day of each treatment cycle 2 Doxorubicin. In some specific embodiments, in the said use or method, every 3 weeks is a treatment cycle, and on the first day of each treatment cycle, 100 mg of an anti-CD40 antibody or its antigen-binding fragment is administered, and 75 mg / m is administered on the first day of each treatment cycle 2 Doxorubicin.

[0095] In some embodiments, in the said use or method, the dosing regimens (such as dosing cycles, dosing doses and dose adjustments) of the anti-CD40 antibody or its antigen-binding fragment, anti-PD-1 antibody or its antigen-binding fragment (e.g., penpulimab) and anthracyclines (e.g., doxorubicin) can be adjusted according to the severity of the disease, the response of the disease, any treatment-related toxicities, the age and health status of the patient. For example, a treatment cycle of the anti-CD40 antibody or its antigen-binding fragment and / or anti-PD-1 antibody or its antigen-binding fragment can be adjusted to 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks or 15 weeks.

[0096] Anti-CD40 antibody or its antigen-binding fragment

[0097] As used in the present application, the anti-CD40 antibody or its antigen-binding fragment comprises: heavy chain CDR1 (HCDR1) of the amino acid sequence shown in SEQ ID NO:1, HCDR2 of the amino acid sequence shown in SEQ ID NO:2, HCDR3 of the amino acid sequence shown in SEQ ID NO:3, light chain CDR1 (LCDR1) of the amino acid sequence shown in SEQ ID NO:4, LCDR2 of the amino acid sequence shown in SEQ ID NO:5, and LCDR3 of the amino acid sequence shown in SEQ ID NO:6.

[0098] In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO:7 or 8. In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO:9 or 10.

[0099] In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO:7 or 8, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO:9 or 10. In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO:9. In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO:8, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO:9.In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO:10. In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO:8, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO:10.

[0100] In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises: an HCDR1 comprising the amino acid sequence shown in SEQ ID NO:1, an HCDR2 comprising the amino acid sequence shown in SEQ ID NO:2, an HCDR3 comprising the amino acid sequence shown in SEQ ID NO:3, an LCDR1 comprising the amino acid sequence shown in SEQ ID NO:4, an LCDR2 comprising the amino acid sequence shown in SEQ ID NO:5, and an LCDR3 comprising the amino acid sequence shown in SEQ ID NO:6; and the anti-CD40 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO:8, and a light chain variable region having an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO:9.

[0101] In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having the amino acid sequence shown in SEQ ID NO:7 or 8, and a light chain variable region having the amino acid sequence shown in SEQ ID NO:9 or 10. In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region having the amino acid sequence shown in SEQ ID NO:9. In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having the amino acid sequence shown in SEQ ID NO:8, and a light chain variable region having the amino acid sequence shown in SEQ ID NO:9. In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having the amino acid sequence shown in SEQ IDNO:7, and a light chain variable region having the amino acid sequence shown in SEQ ID NO:10. In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having the amino acid sequence shown in SEQ ID NO:8, and a light chain variable region having the amino acid sequence shown in SEQ ID NO:10.

[0102] In some specific embodiments, the amino acid sequence of the heavy chain variable region of the anti-CD40 antibody or its antigen-binding fragment is as shown in SEQ ID NO:7, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO:9. In some specific embodiments, the amino acid sequence of the heavy chain variable region of the anti-CD40 antibody or its antigen-binding fragment is as shown in SEQ ID NO:8, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO:9. In some specific embodiments, the amino acid sequence of the heavy chain variable region of the anti-CD40 antibody or its antigen-binding fragment is as shown in SEQ ID NO:7, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO:10. In some specific embodiments, the amino acid sequence of the heavy chain variable region of the anti-CD40 antibody or its antigen-binding fragment is as shown in SEQ ID NO:8, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO:10.

[0103] In some embodiments, the anti-CD40 antibody or its antigen-binding fragment comprises a heavy chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO:11 or 12. In some embodiments, the anti-CD40 antibody or its antigen-binding fragment comprises a light chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO:13 or 14.

[0104] In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO: 11 or 12, and a light chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO: 13 or 14. In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO: 11, and a light chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO: 13. In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO: 12, and a light chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO: 13.In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO:11, and a light chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO:14. In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO:12, and a light chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO:14.

[0105] In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises a heavy chain having the amino acid sequence shown in SEQ ID NO:11 or 12, and a light chain having the amino acid sequence shown in SEQ ID NO:13 or 14. In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises a heavy chain having the amino acid sequence shown in SEQ ID NO:11, and a light chain having the amino acid sequence shown in SEQ ID NO:13. In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises a heavy chain having the amino acid sequence shown in SEQ ID NO:12, and a light chain having the amino acid sequence shown in SEQ ID NO:13. In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises a heavy chain having the amino acid sequence shown in SEQ ID NO:11, and a light chain having the amino acid sequence shown in SEQ ID NO:14. In some embodiments, the anti-CD40 antibody or antigen-binding fragment thereof comprises a heavy chain having the amino acid sequence shown in SEQ ID NO:12, and a light chain having the amino acid sequence shown in SEQ ID NO:14.

[0106] In some specific embodiments, the amino acid sequence of the heavy chain of the anti-CD40 antibody or its antigen-binding fragment is as shown in SEQ ID NO:11, and the amino acid sequence of the light chain is as shown in SEQ ID NO:13. In some specific embodiments, the amino acid sequence of the heavy chain of the anti-CD40 antibody or its antigen-binding fragment is as shown in SEQ ID NO:12, and the amino acid sequence of the light chain is as shown in SEQ ID NO:13. In some specific embodiments, the amino acid sequence of the heavy chain of the anti-CD40 antibody or its antigen-binding fragment is as shown in SEQ ID NO:11, and the amino acid sequence of the light chain is as shown in SEQ ID NO:14. In some specific embodiments, the amino acid sequence of the heavy chain of the anti-CD40 antibody or its antigen-binding fragment is as shown in SEQ ID NO:12, and the amino acid sequence of the light chain is as shown in SEQ ID NO:14.

[0107] Table 1. CDR and variable region sequence IDs of the anti-CD40 antibody or its antigen-binding fragment

[0108]

[0109] Those skilled in the art should understand that, unless otherwise specified, the term "CDR" or "complementary determining region" of a given antibody or its region (such as the variable region) should be understood to cover the complementary determining regions defined by any known scheme. Although Table 1 has shown the CDR sequences defined by the Kabat numbering system, however, as is well known in the art, the CDR regions can also be determined by other numbering systems such as Chothia, IMGT, CCG, AbM or Contact numbering system / method based on the heavy / light chain variable region sequences. Those skilled in the art should understand that, unless otherwise specified, the terms "CDR" and "complementary determining region" of a given antibody or its region (such as the variable region) should be understood to cover the "CDR" and "complementary determining region" defined by any known scheme. Although the scope claimed in this application is based on the sequences shown in Table 1, the amino acid sequences defined by other CDR numbering systems should also fall within the protection scope of this application. When the anti-CD40 antibody or its antigen-binding fragment is defined by specific CDR sequences in this application, the scope of the anti-CD40 antibody or its antigen-binding fragment covers the anti-CD40 antibody or its antigen-binding fragment defined by the CDR sequences defined by any known scheme.

[0110] In some other embodiments, the anti-CD40 antibody or its antigen-binding fragment is selected from: Dacetuzumab, Lucatumumab, APX005M, CDX-1140 (Celldex), GEN-1042 (BioNTech; Genmab), Selicrelumab, SEA-CD40 (Seagen), 2141-v11 (AbbVie), ChiLob7 / 4 (BioNTech), Mitazalimab, Vanalimab, Giloralimab, LVGN-7409 (LegoChem Biosciences), LVGN-7408 (LegoChem Biosciences), YH003 (Huhe Pharma), SHR-1704 (Jiangsu Hengrui Medicine), MIL97 (Tianguangshi Biosciences), Iscalimab, Bleselumab, Ravagalimab, or an antigen-binding fragment of the above antibodies.

[0111] Anti-PD-1 antibody or its antigen-binding fragment

[0112] As used in the present application, the anti-PD-1 antibody or its antigen-binding fragment comprises: HCDR1 with the amino acid sequence shown in SEQ ID NO:15, HCDR2 with the amino acid sequence shown in SEQ ID NO:16, HCDR3 with the amino acid sequence shown in SEQ ID NO:17, LCDR1 with the amino acid sequence shown in SEQ ID NO:18, LCDR2 with the amino acid sequence shown in SEQ ID NO:19, and LCDR3 with the amino acid sequence shown in SEQ ID NO:20.

[0113] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO:21. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a light chain variable region having an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO:22.

[0114] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 21, and a light chain variable region having an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 22.

[0115] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 15, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 16, HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 17, LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 18, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 19, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 20; and, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 21, and a light chain variable region having an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 22.

[0116] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having the amino acid sequence shown in SEQ ID NO: 21, and a light chain variable region having the amino acid sequence shown in SEQ ID NO: 22.

[0117] In some specific embodiments, the amino acid sequence of the heavy chain variable region of the anti-PD-1 antibody or antigen-binding fragment thereof is as shown in SEQ ID NO: 21, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO: 22.

[0118] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO: 23. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO: 24.

[0119] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO: 23, and a light chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO: 24.

[0120] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain of the amino acid sequence shown in SEQ ID NO: 23, and a light chain of the amino acid sequence shown in SEQ ID NO: 24.

[0121] In some specific embodiments, the amino acid sequence of the heavy chain of the anti-PD-1 antibody or antigen-binding fragment thereof is as shown in SEQ ID NO: 23, and the amino acid sequence of the light chain is as shown in SEQ ID NO: 24.

[0122] Table 2. Sequence IDs of anti-PD-1 antibodies or antigen-binding fragments thereof

[0123]

[0124] Those skilled in the art should understand that, unless otherwise specified, the term "CDR" or "complementary determining region" of a given antibody or its region (such as the variable region) should be understood to cover the complementary determining regions defined by any known scheme. Although the CDR regions are shown in Table 2, however, when it comes to defining an anti-PD-1 antibody or its antigen-binding fragment with a specific CDR sequence, the scope of the anti-PD-1 antibody or its antigen-binding fragment covers the anti-PD-1 antibody or its antigen-binding fragment defined by the CDR sequence defined by any numbering system (such as the combination of one or more of the definitions known in the art, such as AbM, Kabat, CCG, Chothia, IMGT or Contact, etc.).

[0125] In some other embodiments, the anti-PD-1 antibody or its antigen-binding fragment of the present application is selected from: Nivolumab, Pembrolizumab, Toripalimab, Sintilimab, Camrelizumab, Tislelizumab, Zimberelimab, Balstilimab, geptanolimab, Lipustobart (LZM-009) of Livzon Pharmaceutical, Cemiplimab, Serplulimab, Prolgolimab, Putrilimab (HX008), Nofazinlimab, Finotonlimab, Dostarlimab, Cetrelimab, QL1604 of Qilu Pharmaceutical, Spartalizumab, Retifanlimab, Sasanlimab, Rulonilimab (F520) of Shandong New Times Pharmaceutical Co., Ltd., or Enlonstobart (SG001) of ShangJian Biotech Co., Ltd.

[0126] Chemotherapeutic drug

[0127] In some embodiments, the chemotherapeutic drugs include, but are not limited to, platinum-based drugs (including but not limited to oxaliplatin, cisplatin, carboplatin, nedaplatin, bicispate, miboplatin, lobaplatin, picoplatin, Lobaplatin, triplatin tetranitrate, phenanthriplatin, satraplatin), camptothecin-based drugs (including but not limited to camptothecin, hydroxycamptothecin, aminocamptothecin, irinotecan, topotecan, exatecan, rubitecan, lurtotecan, gimitecan, karenitecin, 7-ethylcamptothecin), taxanes (including but not limited to paclitaxel, liposomal paclitaxel, albumin-bound paclitaxel, and docetaxel), nitrogen mustards (including but not limited to cyclophosphamide, ifosfamide, chlorambucil, carmustine, melphalan, bendamustine), antimetabolites (including but not limited to fluorouracil-based drugs (including but not limited to carmofur, 5-fluorouracil, tegafur, capecitabine, tegafur-uracil, ftorafur, doxifluridine, trifluridine), cytosine-based drugs (including but not limited to cytarabine, gemcitabine, azacitidine, ancitabine), purine-based drugs (including but not limited to mercaptopurine, fludarabine), antifolates (including but not limited to methotrexate, pemetrexed)), anthracyclines (including but not limited to doxorubicin, epirubicin, pirarubicin, amrubicin, aclarubicin, idarubicin, daunorubicin, mitoxantrone, idamycin, valrubicin, zorubicin, pixantrone, liposomal doxorubicin), vinca alkaloids (including but not limited to vinblastine, vincristine, vindesine, vinflunine, and vinorelbine), podophyllotoxin alkaloids (including but not limited to etoposide, teniposide), hormones (including but not limited to prednisone, prednisolone, dexamethasone, methylprednisolone sodium succinate), procarbazine, altretamine, dacarbazine, mitomycin, actinomycin D (dactinomycin), bleomycin, pingyangmycin, temozolomide, dacarbazine, peplomycin, eribulin, plinabulin, Sapacitabine, treosulfan, 153Sm-EDTMP, and encequidar, or one or more of them.

[0128] In some embodiments, the chemotherapeutic drug is selected from one or more of platinum-based drugs, taxanes, anthracyclines, and antimetabolites. In some embodiments, the chemotherapeutic drug is an anthracycline.

[0129] Representative anthracyclines include, but are not limited to: doxorubicin, epirubicin, pirarubicin, amrubicin, aclarubicin, idarubicin, daunorubicin, mitoxantrone, idamycin, valrubicin, zorubicin, pixantrone, liposomal doxorubicin, or any combination of the foregoing. In some specific embodiments, the anthracyclines include doxorubicin, epirubicin, mitoxantrone, and daunorubicin. In some specific embodiments, the anthracyclines include doxorubicin. In some specific embodiments, the doxorubicin includes liposomal doxorubicin.

[0130] Mode of administration

[0131] The following does not limit the administration methods of the drug combinations of the present application.

[0132] Each component in the drug combinations of the present application can be administered independently, or some or all of them together, by various suitable routes, including but not limited to oral or parenteral (e.g., by intravenous, intramuscular, topical, or subcutaneous routes) administration. In some embodiments, each component of the drug combinations of the present application can be administered independently, or some or all of them together, by oral administration or injection, such as intramuscular injection, intravenous injection, subcutaneous injection, intratumoral injection, or intraperitoneal injection.

[0133] The components in the pharmaceutical compositions of the present application can be prepared independently, or some or all of them together, into suitable dosage forms, including but not limited to tablets, lozenges, pills, capsules (e.g., hard capsules, soft capsules, enteric-coated capsules, microcapsules), tinctures, granules, syrups, injections (e.g., intramuscular, intravenous, subcutaneous, intratumoral, or intraperitoneal injections), granules, emulsions, suspensions, solutions, dispersions, and dosage forms for sustained-release preparations for oral or non-oral administration.

[0134] The components in the drug combinations of the present application can independently, or some or all of them together, contain pharmaceutically acceptable carriers and / or excipients.

[0135] The drug combinations of the present application can also contain additional therapeutic agents. In one embodiment, the additional therapeutic agent can be a tumor therapeutic agent known in the art.

[0136] Tumor

[0137] The "tumor" referred to in the present application is a malignant tumor (i.e., cancer); the malignant tumor refers to any malignant and / or invasive growth caused by abnormal cell growth.

[0138] In some embodiments, the tumor is a solid tumor. In some embodiments, the tumor is a treatment-naive, inoperable or surgery-refusing, refractory, advanced, recurrent, and / or metastatic tumor. In some embodiments, the tumor is an inoperable or surgery-refusing tumor. In some embodiments, the tumor is a refractory tumor. In some embodiments, the tumor is an advanced tumor. In some embodiments, the tumor is a locally advanced tumor. In some embodiments, the tumor is a recurrent tumor. In some embodiments, the tumor is a metastatic tumor. In some embodiments, the tumor is an advanced, metastatic, and / or recurrent tumor. In some embodiments, the tumor is a locally advanced, metastatic, and / or recurrent tumor. In some embodiments, the tumor is an inoperable or surgery-refusing, locally advanced, metastatic, and / or recurrent tumor. In some embodiments, the tumor is an inoperable or surgery-refusing locally advanced, metastatic, and / or recurrent tumor.

[0139] In some embodiments, the tumor is a soft tissue sarcoma. In some embodiments, the tumor is a treatment-naive, inoperable or surgery-refusing, refractory, advanced, recurrent, and / or metastatic soft tissue sarcoma. In some embodiments, the tumor is an inoperable or surgery-refusing soft tissue sarcoma. In some embodiments, the tumor is a refractory soft tissue sarcoma. In some embodiments, the tumor is an advanced soft tissue sarcoma. In some embodiments, the tumor is a locally advanced soft tissue sarcoma. In some embodiments, the tumor is a recurrent soft tissue sarcoma. In some embodiments, the tumor is a metastatic soft tissue sarcoma. In some embodiments, the tumor is an advanced, metastatic, and / or recurrent soft tissue sarcoma. In some embodiments, the tumor is a locally advanced, metastatic, and / or recurrent soft tissue sarcoma. In some embodiments, the tumor is an inoperable or surgery-refusing, locally advanced, metastatic, and / or recurrent soft tissue sarcoma. In some embodiments, the tumor is an inoperable or surgery-refusing locally advanced, metastatic, and / or recurrent soft tissue sarcoma.

[0140] In some embodiments, the soft tissue sarcoma includes, but is not limited to, liposarcoma, leiomyosarcoma, malignant fibrous histiocytoma, fibrosarcoma, rhabdomyosarcoma, synovial sarcoma, dermatofibrosarcoma protuberans, malignant peripheral nerve sheath tumor, alveolar soft part sarcoma, clear cell sarcoma, angiosarcoma, malignant mesenchymoma, epithelioid sarcoma, and undifferentiated sarcoma (e.g., undifferentiated pleomorphic sarcoma). In some embodiments, the soft tissue sarcoma includes, but is not limited to, liposarcoma, leiomyosarcoma, undifferentiated pleomorphic sarcoma / malignant fibrous histiocytoma, fibrosarcoma, synovial sarcoma, alveolar soft part sarcoma, clear cell sarcoma, and epithelioid sarcoma. In some embodiments, the soft tissue sarcoma includes, but is not limited to, liposarcoma, leiomyosarcoma, and undifferentiated pleomorphic sarcoma. In some specific embodiments, the soft tissue sarcoma is selected from dedifferentiated liposarcoma, well-differentiated liposarcoma with a dedifferentiated component, undifferentiated pleomorphic sarcoma, and leiomyosarcoma. In some specific embodiments, the soft tissue sarcoma is dedifferentiated liposarcoma. In some specific embodiments, the soft tissue sarcoma is well-differentiated liposarcoma with a dedifferentiated component. In some specific embodiments, the soft tissue sarcoma is leiomyosarcoma. In some specific embodiments, the soft tissue sarcoma is leiomyosarcoma excluding uterine leiomyosarcoma. In some specific embodiments, the soft tissue sarcoma is undifferentiated pleomorphic sarcoma.

[0141] In some embodiments, the soft tissue sarcoma is an untreated soft tissue sarcoma (e.g., lacking an effective treatment regimen). In some embodiments, the soft tissue sarcoma is a soft tissue sarcoma that has not been treated with surgery, radiotherapy, chemotherapy, and / or immunotherapy.

[0142] In some embodiments, the soft tissue sarcoma is a soft tissue sarcoma that has not been previously treated with chemotherapy. In some embodiments, the soft tissue sarcoma is a locally advanced, metastatic, and / or recurrent soft tissue sarcoma that has not been previously treated with chemotherapy. In some embodiments, the soft tissue sarcoma is a locally advanced, metastatic, and / or recurrent liposarcoma and leiomyosarcoma that has not been previously treated with chemotherapy. In some embodiments, the soft tissue sarcoma is an inoperable or surgically refused, locally advanced, metastatic, and / or recurrent liposarcoma and leiomyosarcoma that has not been previously treated with chemotherapy. In some embodiments, the soft tissue sarcoma is a dedifferentiated liposarcoma, well-differentiated liposarcoma with a dedifferentiated component, and leiomyosarcoma that has not been previously treated with chemotherapy. In some embodiments, the soft tissue sarcoma is an inoperable or surgically refused, locally advanced, metastatic, and / or recurrent dedifferentiated liposarcoma, well-differentiated liposarcoma with a dedifferentiated component, and leiomyosarcoma that has not been previously treated with chemotherapy.

[0143] In some embodiments, the soft tissue sarcoma is a soft tissue sarcoma that has not previously received anthracycline chemotherapy. In some embodiments, the soft tissue sarcoma is a locally advanced, metastatic, and / or recurrent soft tissue sarcoma that has not previously received anthracycline chemotherapy. In some embodiments, the soft tissue sarcoma is a locally advanced, metastatic, and / or recurrent liposarcoma and leiomyosarcoma that has not previously received anthracycline chemotherapy. In some embodiments, the soft tissue sarcoma is an inoperable or surgery-refusing, locally advanced, metastatic, and / or recurrent liposarcoma and leiomyosarcoma that has not previously received anthracycline chemotherapy. In some embodiments, the soft tissue sarcoma is a dedifferentiated liposarcoma, well-differentiated liposarcoma with a dedifferentiated component, and leiomyosarcoma that has not previously received anthracycline chemotherapy. In some embodiments, the soft tissue sarcoma is an inoperable or surgery-refusing, locally advanced, metastatic, and / or recurrent dedifferentiated liposarcoma, well-differentiated liposarcoma with a dedifferentiated component, and leiomyosarcoma that has not previously received anthracycline chemotherapy.

[0144] In some embodiments, the soft tissue sarcoma is a soft tissue sarcoma with no history of anthracycline chemotherapy failure. In some embodiments, the soft tissue sarcoma is a locally advanced, metastatic, and / or recurrent soft tissue sarcoma with no history of anthracycline chemotherapy failure. In some embodiments, the soft tissue sarcoma is a locally advanced, metastatic, and / or recurrent liposarcoma and leiomyosarcoma with no history of anthracycline chemotherapy failure. In some embodiments, the soft tissue sarcoma is an inoperable or surgery-refusing, locally advanced, metastatic, and / or recurrent liposarcoma and leiomyosarcoma with no history of anthracycline chemotherapy failure. In some embodiments, the soft tissue sarcoma is a dedifferentiated liposarcoma, well-differentiated liposarcoma with a dedifferentiated component, and leiomyosarcoma with no history of anthracycline chemotherapy failure. In some embodiments, the soft tissue sarcoma is an inoperable or surgery-refusing, locally advanced, metastatic, and / or recurrent dedifferentiated liposarcoma, well-differentiated liposarcoma with a dedifferentiated component, and leiomyosarcoma with no history of anthracycline chemotherapy failure.

[0145] In some embodiments, the soft tissue sarcoma is a soft tissue sarcoma that has previously received one or more different anti-tumor therapies (e.g., treatment failure or inapplicable). In some embodiments, the soft tissue sarcoma is a soft tissue sarcoma that has previously received surgery, radiotherapy, chemotherapy, and / or immunotherapy (e.g., treatment failure or inapplicable). In some embodiments, the soft tissue sarcoma is a soft tissue sarcoma that has previously received no more than two anti-tumor therapies (e.g., treatment failure or inapplicable). In some embodiments, the soft tissue sarcoma is a soft tissue sarcoma that has previously received first-line or second-line treatment (e.g., treatment failure or inapplicable). In some embodiments, the soft tissue sarcoma is a soft tissue sarcoma that has previously received systemic treatment (e.g., treatment failure or inapplicable). In some embodiments, the soft tissue sarcoma is a soft tissue sarcoma that has previously received chemotherapy (e.g., treatment failure or inapplicable). In some embodiments, the soft tissue sarcoma is a locally advanced, metastatic, and / or recurrent soft tissue sarcoma that has previously received chemotherapy (e.g., treatment failure or inapplicable). In some embodiments, the soft tissue sarcoma is a non-surgical or surgery-refusing, locally advanced, metastatic, and / or recurrent soft tissue sarcoma that has previously received chemotherapy (e.g., treatment failure or inapplicable). In some embodiments, the soft tissue sarcoma is a soft tissue sarcoma that has previously received an anti-angiogenic drug or a tyrosine kinase inhibitor (e.g., treatment failure or inapplicable). In some embodiments, the soft tissue sarcoma is a locally advanced, metastatic, and / or recurrent soft tissue sarcoma that has previously received an anti-angiogenic drug or a tyrosine kinase inhibitor (e.g., treatment failure or inapplicable). In some embodiments, the soft tissue sarcoma is a non-surgical or surgery-refusing, locally advanced, metastatic, and / or recurrent soft tissue sarcoma that has previously received an anti-angiogenic drug or a tyrosine kinase inhibitor (e.g., treatment failure or inapplicable).

[0146] In some embodiments, the soft tissue sarcoma is a soft tissue sarcoma with chemotherapy failure (e.g., treatment failure or inapplicable). In some embodiments, the soft tissue sarcoma is a locally advanced, metastatic, and / or recurrent soft tissue sarcoma with chemotherapy failure (e.g., treatment failure or inapplicable). In some embodiments, the soft tissue sarcoma is a non-surgical or surgery-refusing, locally advanced, metastatic, and / or recurrent soft tissue sarcoma with chemotherapy failure (e.g., treatment failure or inapplicable). In some embodiments, the soft tissue sarcoma is a non-surgical or surgery-refusing, locally advanced, metastatic, and / or recurrent undifferentiated pleomorphic sarcoma with chemotherapy failure (e.g., treatment failure or inapplicable).

[0147] In some embodiments, the soft tissue sarcoma is a soft tissue sarcoma that has failed anthracycline chemotherapy. In some embodiments, the soft tissue sarcoma is a locally advanced, metastatic, and / or recurrent soft tissue sarcoma that has failed anthracycline chemotherapy. In some embodiments, the soft tissue sarcoma is an inoperable or surgery-refusing, locally advanced, metastatic, and / or recurrent soft tissue sarcoma that has failed anthracycline chemotherapy. In some embodiments, the soft tissue sarcoma is an undifferentiated pleomorphic sarcoma that has failed anthracycline chemotherapy. In some embodiments, the soft tissue sarcoma is an inoperable or surgery-refusing, locally advanced, metastatic, and / or recurrent undifferentiated pleomorphic sarcoma that has failed anthracycline chemotherapy.

[0148] In some embodiments, the soft tissue sarcoma is a soft tissue sarcoma that has failed anti-angiogenic drug or tyrosine kinase inhibitor therapy. In some embodiments, the soft tissue sarcoma is a locally advanced, metastatic, and / or recurrent soft tissue sarcoma that has failed anti-angiogenic drug or tyrosine kinase inhibitor therapy. In some embodiments, the soft tissue sarcoma is an inoperable or surgery-refusing, locally advanced, metastatic, and / or recurrent soft tissue sarcoma that has failed anti-angiogenic drug or tyrosine kinase inhibitor therapy. In some embodiments, the soft tissue sarcoma is an undifferentiated pleomorphic sarcoma that has failed anti-angiogenic drug or tyrosine kinase inhibitor therapy. In some embodiments, the soft tissue sarcoma is an inoperable or surgery-refusing, locally advanced, metastatic, and / or recurrent undifferentiated pleomorphic sarcoma that has failed anti-angiogenic drug or tyrosine kinase inhibitor therapy.

[0149] The term "anti-angiogenic drug" refers to any drug that can inhibit the process of new blood vessel growth from existing blood vessels (angiogenesis). A tyrosine kinase inhibitor refers to any drug that can inhibit tyrosine kinase or downstream signal transduction from tyrosine kinase. In some embodiments, the anti-angiogenic drug or tyrosine kinase inhibitor includes, but is not limited to, Anlotinib, Vandetanib, Sorafenib, Cediranib, Vatalanib, Pazopanib, Regorafenib, Motesanib, Lenvatinib, Sunitinib, Bevacizumab, Ramucirumab, or a pharmaceutically acceptable salt thereof, or any combination of the foregoing.

[0150] In some embodiments, the tumor is melanoma. In some embodiments, the tumor is treatment-naive, inoperable or refuses surgery, refractory, advanced, recurrent, and / or metastatic melanoma. In some embodiments, the tumor is inoperable or refuses surgery melanoma. In some embodiments, the tumor is refractory melanoma. In some embodiments, the tumor is advanced melanoma. In some embodiments, the tumor is locally advanced melanoma. In some embodiments, the tumor is recurrent melanoma. In some embodiments, the tumor is metastatic melanoma. In some embodiments, the tumor is advanced, metastatic, and / or recurrent melanoma. In some embodiments, the tumor is locally advanced, metastatic, and / or recurrent melanoma. In some embodiments, the tumor is inoperable or refuses surgery, locally advanced, metastatic, and / or recurrent melanoma. In some embodiments, the tumor is inoperable or refuses surgery, locally advanced, metastatic, and / or recurrent melanoma.

[0151] In some embodiments, the melanoma is untreated melanoma (e.g., lack of effective treatment regimens). In some embodiments, the melanoma is untreated by surgery, radiotherapy, chemotherapy, and / or immunotherapy.

[0152] In some embodiments, the melanoma is melanoma that has previously received one or more different anti-tumor therapies (e.g., treatment failure or inapplicable). In some embodiments, the melanoma is melanoma that has previously received surgery, radiotherapy, chemotherapy, and / or immunotherapy (e.g., treatment failure or inapplicable). In some embodiments, the melanoma is melanoma that has previously received no more than two anti-tumor therapies (e.g., treatment failure or inapplicable). In some embodiments, the melanoma is melanoma that has previously received first-line or second-line treatment (e.g., treatment failure or inapplicable). In some embodiments, the melanoma is melanoma that has previously received systemic treatment (e.g., treatment failure or inapplicable).

[0153] In some embodiments, the melanoma is a melanoma that has previously received targeted therapy (e.g., treatment failure or inapplicable). In some embodiments, the melanoma is a locally advanced, metastatic, and / or recurrent melanoma that has previously received targeted therapy (e.g., treatment failure or inapplicable). In some embodiments, the melanoma is a non-surgical or surgically-inadvisable, locally advanced, metastatic, and / or recurrent melanoma that has previously received targeted therapy (e.g., treatment failure or inapplicable). In some embodiments, the melanoma is a melanoma with targeted therapy failure. In some embodiments, the melanoma is a locally advanced, metastatic, and / or recurrent melanoma with targeted therapy failure. In some embodiments, the melanoma is a non-surgical or surgically-inadvisable, locally advanced, metastatic, and / or recurrent melanoma with targeted therapy failure. In some embodiments, the targeted therapy drugs include, but are not limited to, BRAF inhibitors, MEK inhibitors, and KIT inhibitors, such as Vemurafenib, Dabrafenib, Trametinib, Cobimetinib, Binimetinib, Encorafenib, Imatinib, and Nilotinib.

[0154] In some embodiments, the melanoma is a melanoma that has previously received chemotherapy (e.g., treatment failure or inapplicable). In some embodiments, the melanoma is a locally advanced, metastatic, and / or recurrent melanoma that has previously received chemotherapy (e.g., treatment failure or inapplicable). In some embodiments, the melanoma is a non-surgical or surgically-inadvisable, locally advanced, metastatic, and / or recurrent melanoma that has previously received chemotherapy (e.g., treatment failure or inapplicable). In some embodiments, the melanoma is a melanoma with chemotherapy failure. In some embodiments, the melanoma is a locally advanced, metastatic, and / or recurrent melanoma with chemotherapy failure. In some embodiments, the melanoma is a non-surgical or surgically-inadvisable, locally advanced, metastatic, and / or recurrent melanoma with chemotherapy failure.

[0155] In some embodiments, the melanoma is a melanoma that has previously received immunotherapy (e.g., treatment failure or inapplicability). In some embodiments, the melanoma is a locally advanced, metastatic, and / or recurrent melanoma that has previously received immunotherapy (e.g., treatment failure or inapplicability). In some embodiments, the melanoma is a non-surgical or surgically refused, locally advanced, metastatic, and / or recurrent melanoma that has previously received immunotherapy (e.g., treatment failure or inapplicability). In some embodiments, the immunotherapy drugs include, but are not limited to, immune checkpoint inhibitors, cytokines, vaccines, immune cell therapies, etc. In some embodiments, the melanoma is a melanoma that has previously received an immune checkpoint inhibitor (e.g., treatment failure or inapplicability). In some embodiments, the melanoma is a locally advanced, metastatic, and / or recurrent melanoma that has previously received an immune checkpoint inhibitor (e.g., treatment failure or inapplicability). In some embodiments, the melanoma is a non-surgical or surgically refused, locally advanced, metastatic, and / or recurrent melanoma that has previously received an immune checkpoint inhibitor (e.g., treatment failure or inapplicability). In some embodiments, the melanoma is a melanoma that has failed immunotherapy with an immune checkpoint inhibitor. In some embodiments, the melanoma is a locally advanced, metastatic, and / or recurrent melanoma that has failed immunotherapy with an immune checkpoint inhibitor. In some embodiments, the melanoma is a non-surgical or surgically refused, locally advanced, metastatic, and / or recurrent melanoma that has failed immunotherapy with an immune checkpoint inhibitor.

[0156] In some embodiments, the melanoma includes cutaneous melanoma or mucosal melanoma. In some embodiments, the melanoma is acral melanoma, such as acral malignant melanoma. In some embodiments, the melanoma includes acral melanoma with the primary site on the sole of the foot, toes, fingertips, or under the nails.

[0157] Technical effect

[0158] (1) Generally, using the drug combination of the present application, huC1H1-V2 and doxorubicin, or huC1H1-V2 and pamiparlimab will help to:

[0159] produce better efficacy in reducing tumor growth or even eliminating the tumor compared to administering any one of the drugs alone;

[0160] (2) Provide a smaller amount of administration compared to administering any one of the drugs alone;

[0161] (3) Provide a treatment that is well tolerated in patients, with fewer adverse reactions and / or complications compared to any one of the drugs administered alone.

[0162] (4) Provide a better disease control rate among the treated patients;

[0163] (5) Provide a longer survival period (such as median survival, progression-free survival or overall survival) for the treated patients;

[0164] (6) Provide a longer survival period (such as median survival, progression-free survival or overall survival) for the treated patients compared to standard chemotherapy;

[0165] (7) Provide a longer duration of disease remission (DOR); and / or

[0166] (8) Have good anti-tumor activity compared to administering any one of the drugs in the combination alone, showing more excellent anti-tumor synergistic effects.

[0167] The drug combination and treatment regimen of the present application have good curative effects in the treatment of tumors, especially soft tissue sarcoma and melanoma, and have beneficial effects in at least one aspect of at least ORR, DCR, CBR, DOR, PFS, OS, 12m-PFS, 6m-PFS, tolerance and side effects.

[0168] The combination of huC1H1-V2 and doxorubicin of the present application can safely and effectively treat locally advanced, recurrent or metastatic soft tissue sarcoma, and has beneficial effects in at least one aspect of at least ORR, DCR, CBR, DOR, PFS, OS, 12m-PFS, 6m-PFS, tolerance and side effects.

[0169] The combination of huC1H1-V2 and pamiparib of the present application can safely and effectively treat locally advanced, recurrent or metastatic soft tissue sarcoma (especially undifferentiated pleomorphic sarcoma) and melanoma, and has beneficial effects in at least one aspect of at least ORR, DCR, CBR, DOR, PFS, OS, 12m-PFS, 6m-PFS, tolerance and side effects.

[0170] Definition and description

[0171] To better understand the present invention, some terms are first defined. Other definitions are listed throughout the detailed description. Unless otherwise specified, the following terms used in the present application have the following meanings. A particular term should not be considered indeterminate or unclear without a specific definition, but should be understood according to the ordinary meaning in the art. When a trade name appears in the present application, it is intended to refer to its corresponding product or its active ingredient.

[0172] As used herein, the term "antibody" refers to an antigen-binding protein having at least one antigen-binding domain. The antibodies and fragments thereof of the present application can be whole antibodies or any fragments thereof. Thus, the antibodies and fragments thereof of the present application include monoclonal antibodies or fragments thereof and antibody variants or fragments thereof. Examples of antibodies and antigen-binding fragments thereof include monospecific antibodies, bispecific antibodies, multispecific antibodies, single-domain antibodies, Fab fragments, Fab' fragments, F(ab')2 fragments, Fv fragments, isolated CDR regions, single-chain Fv molecules (scFv), and other antibody fragments known in the art. The anti-CD40 antibodies and antigen-binding fragments thereof and anti-PD-1 antibodies and antigen-binding fragments thereof disclosed herein can be of the IgG1, IgG2, IgG3, or IgG4 isotype. The term "isotype" refers to the classes of antibodies encoded by heavy-chain constant region genes. The anti-CD40 antibodies and antigen-binding fragments thereof and anti-PD-1 antibodies and antigen-binding fragments thereof of the present application can be derived from any species, including but not limited to mice, rats, rabbits, primates, camels, and humans. The anti-CD40 antibodies and antigen-binding fragments thereof and anti-PD-1 antibodies and antigen-binding fragments thereof of the present application can be murine antibodies, chimeric antibodies, humanized antibodies, or fully human antibodies. Unless otherwise specified, the "antibodies" of the present application include whole antibodies and any antigen-binding fragments or single chains thereof. A conventional "whole antibody" is a glycoprotein comprising two heavy (H) chains and two light (L) chains, which are linked by disulfide bonds. Each heavy chain consists of a heavy-chain variable region (V H ) and a heavy-chain constant region (C H ). The heavy-chain constant region consists of three domains, namely C H1 , C H2 , and C H3 . Each light chain consists of a light-chain variable region (V L ) and a light-chain constant region (C L ). The light-chain constant region consists of one domain C L . The V H and V L regions can also be divided into hypervariable regions, i.e., complementarity-determining regions (CDRs), and relatively conserved framework regions (FRs). Each V H and V L consists of three CDRs and four FRs, respectively, from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with antigens. The constant region of the antibody can mediate the binding of immunoglobulins to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component of the classical complement system (C1q). At the same time, as is known to those skilled in the art, special "whole antibodies", such as nanobodies, have only heavy (H) chains and no light (L) chains.

[0173] An "antigen-binding fragment" of an antibody refers to one or more fragments of an antibody that retain the function of specifically binding to an antigen. It has been demonstrated that the antigen-binding function of an antibody can be carried out by fragments of the whole antibody. Examples included within the term "antigen-binding fragment" of an antibody are: (i) Fab fragment: a monovalent fragment consisting of the V L and V H , CL and CH1 domains; (ii) F(ab')2 fragment, a divalent fragment containing two Fab fragments linked by a disulfide bridge in the hinge region; (iii) Fd fragment consisting of the VH and CH1 domains; (iv) Fv fragment consisting of the VL and VH domains of a single arm of an antibody; (v) dAb fragment consisting of the VH domain (see Ward et al., Nature. 341:544-546 (1989)); (vi) isolated complementarity-determining regions (CDRs); and (vii) nanobody, a heavy-chain variable region containing a single variable domain and two constant domains. In addition, although the two domains VL and VH of the Fv fragment are encoded by different genes, recombinant methods can be used to link VH and VL into a single protein chain via a synthetic linker, where VL and VH pair to form a monovalent molecule (referred to as single-chain Fv (scFv); see, for example, Bird et al., Science. 242:423-426 (1988); Huston et al., Proc. Natl. Acad. Sci. 85:5879-5883 (1988)). These single-chain antibodies are also included within the term antigen-binding fragment. In addition, recombinant polypeptides, fusion proteins, small modular immunopharmaceuticals (SMIPs), and immunoconjugates containing such antigen-binding fragments are also included within the term antigen-binding fragment.

[0174] A "chimeric antibody" is an antibody that has at least a portion of the heavy-chain variable region and at least a portion of the light-chain variable region derived from one species; and at least a portion of the constant region derived from another species. For example, in one embodiment, a chimeric antibody can comprise murine variable regions and human constant regions.

[0175] "Humanized antibody" refers to an antibody that contains complementarity-determining regions (CDRs) derived from a non-human antibody and framework regions and constant regions derived from a human antibody. For example, an anti-CD40 antibody may contain CDRs derived from one or more murine antibodies and human framework regions and human constant regions. Exemplary humanized antibodies are provided herein. Additional anti-CD40 antibodies or variants thereof containing the HCDRs and LCDRs provided herein can be generated using any human framework sequence and are also included in this application. Additional anti-PD-1 antibodies or variants thereof containing the HCDRs and LCDRs provided herein can be generated using any human framework sequence and are also included in this application. In one embodiment, framework sequences suitable for use in this application include those that are structurally similar to the framework sequences provided herein. Additional modifications can be made in the framework regions to improve the properties of the antibodies provided herein. Such additional framework modifications can include chemical modifications; point mutations to reduce immunogenicity or remove T cell epitopes; or reversion of mutations to residues in the original germline sequence.

[0176] The term "immune checkpoint inhibitor" refers to a molecule that reduces, inhibits, interferes with, or modulates one or more checkpoint proteins, in whole or in part. Checkpoint proteins regulate T cell activation or function. A variety of checkpoint proteins are known, such as CTLA-4 and its ligands CD80 and CD86; PD-1 and its ligands PD-L1 and PD-L2. These proteins are responsible for co-stimulatory or inhibitory interactions in T cell responses. Immune checkpoint proteins regulate and maintain self-tolerance as well as the duration and magnitude of physiological immune responses. Immune checkpoint inhibitors include antibodies or are derived from antibodies.

[0177] The term "identity", also known as consistency. The "percent identity (%)" of an amino acid sequence refers to the percentage of amino acid residues in the sequence to be aligned that are identical to the amino acid residues of the specific amino acid sequence shown herein, after aligning the sequence to be aligned with the specific amino acid sequence shown herein and introducing gaps if necessary to achieve the maximum percent sequence identity, and without considering any conservative substitutions as part of the sequence identity. Alignment of amino acid sequences with identity can be carried out in a variety of ways within the art, such as using BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine the appropriate parameters for aligning sequences, including any algorithms required to obtain the maximum alignment over the full length of the compared sequences. In some embodiments, two nucleic acids or polypeptides described in the present application are substantially identical, which means that when compared and aligned with the highest correspondence, measured using a sequence alignment algorithm or by visual inspection, the two nucleic acids or polypeptides have at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, and in some embodiments at least 95%, 96%, 97%, 98%, 99% nucleotide or amino acid residue identity.

[0178] The term "drug combination" refers to a combination of two or more active ingredients (including administration in the form of their respective active ingredients themselves, or in the form of their respective pharmaceutically acceptable salts or esters and other derivatives, prodrugs) administered in any order. The active ingredients can each be administered to a subject simultaneously as a single preparation, or each as a single preparation in any order sequentially.

[0179] The term "treatment" generally refers to an operation to obtain the desired pharmacological and / or physiological effects. This effect can be prophylactic according to the complete or partial prevention of a disease or its symptoms; and / or therapeutic according to the partial or complete stabilization or cure of a disease and / or the side effects caused by the disease. "Treatment" as used herein encompasses any treatment of a patient's disease, including but not limited to preventing the occurrence or recurrence of a disease, alleviating the symptoms of a disease, reducing any direct or indirect pathological consequences of a disease, preventing the metastasis of a disease, slowing the progression of a disease, improving or alleviating the state of a disease, increasing the frequency and duration of asymptomatic periods, and regressing or improving the prognosis of a disease.

[0180] "Therapeutically effective amount" or "therapeutically effective dose" means any amount of a drug that, when used alone or in combination with another therapeutic agent, protects a subject from the onset of a disease or promotes the regression of a disease, the regression of which is demonstrated by a decrease in the severity of the disease symptoms, an increase in the frequency and duration of the disease symptom-free period, or the prevention of damage or disability caused by affliction with the disease. The ability of a therapeutic agent to promote the regression of a disease can be evaluated using a variety of methods known to a skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy for humans, or by measuring the activity of the agent in in vitro assays.

[0181] The terms "administer" or "administering" mean the physical introduction of a therapeutic agent to a subject using any of a variety of methods and delivery systems known to those of skill in the art. Routes of administration of an antibody or an antigen-binding fragment thereof (e.g., an anti-CD40 antibody or an antigen-binding fragment thereof, an anti-PD-1 antibody or an antigen-binding fragment thereof) include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, such as by injection or infusion. The phrase "parenteral administration" as used herein refers to a mode of administration other than enteral administration, typically by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, and in vivo electroporation. Administration can also be carried out, for example, once, multiple times, and / or over one or more extended time periods.

[0182] The application of the term "flat dose" means a dose administered to a patient without regard to the patient's weight or body surface area (BSA). Thus, a flat dose is specified as an absolute amount of a pharmaceutical agent (e.g., an anti-CD40 antibody or an antigen-binding fragment thereof), rather than as a mg / kg dose. For example, a 60 kg person and a 100 kg person will receive the same dose of an antibody (e.g., 200 mg of an anti-CD40 antibody or an antigen-binding fragment thereof).

[0183] The term "pharmaceutically acceptable" means, with respect to those compounds, materials, compositions and / or dosage forms, that they are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0184] The term "pharmaceutical composition" means a mixture of the compounds of the present application and a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of the present application to a subject. In this context, the terms "pharmaceutical composition" and "formulation" have the same meaning and are used interchangeably.

[0185] As used herein, the terms "subject", "patient", or "subject entity" are used interchangeably. A "subject", "patient", or "subject entity" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In some embodiments, the term "subject", "patient", or "subject entity" is a mammal. In some embodiments, the subject, patient, or subject entity is a mouse. In some embodiments, the subject, patient, or subject entity is a human.

[0186] As used herein, "administered in combination" or "used in combination" means that two or more compounds can be administered to a subject either simultaneously as separate formulations or sequentially in any order as separate formulations.

[0187] The term "single dose" refers to the smallest packaging unit containing a certain amount of a drug. For example, if a box of medicine contains seven tablets, then one tablet is a single dose; or a vial of injection is a single dose. The term "multiple doses" consists of multiple single doses. "Unit dose" refers to the dose of the active ingredient contained in the smallest packaging unit containing a certain amount of a drug. For example, the dose of the antibody contained in a vial of antibody injection is the unit dose.

[0188] As used herein, a "line of treatment" refers to a position in the sequence in which a patient receives different drugs or other treatments. The term "first-line treatment" refers to treating a patient with a drug that can be selected first or is a standard selection according to the patient's condition. "Second-line treatment", "third-line treatment", or "fourth-line treatment" is administered after first-line treatment, second-line treatment, or third-line treatment, respectively. If a patient does not show a positive clinical outcome to first-line treatment, second-line treatment, or third-line treatment, or shows a positive clinical response but then experiences disease progression or recurrence, or the current condition becomes resistant to a previous treatment that had caused a positive clinical response, the patient will receive a subsequent treatment regimen (e.g., second-line treatment, third-line treatment, or fourth-line treatment). Non-limiting examples of clinical outcomes include tumor response, overall survival, progression-free survival, disease-free survival, time to tumor recurrence, time to tumor progression, relative risk, toxicity, or side effects.

[0189] As used herein, "treatment failure" is defined as the occurrence of disease progression or recurrence during or after the last treatment.

[0190] As used herein, "systemic treatment" refers to systemic chemotherapy, whole-body or local radiotherapy.

[0191] The terms "comprise", "comprises" or "comprising" and their English variants such as "comprises" or "comprising" shall be understood in an open, non-exclusive sense, i.e., "including but not limited to".

[0192] As used in this application, "about" or "approximately" means within an acceptable error range determined by a person of ordinary skill in the art for a particular value, which depends in part on how the value is measured or determined, i.e., the limitations of the measuring system. For example, "about" or "approximately" may represent within 1 standard deviation or more than 1 standard deviation according to the practice in the art. Alternatively, "about" or "approximately" may represent a range of up to ±5%, such as fluctuating within a range of ±2%, ±1% or ±0.5% of a given specific numerical value. When a specific value is given in this application or in the claims, unless otherwise specified, the meaning of "about" or "approximately" should be considered to be within the acceptable error range of that specific value. In this document, unless otherwise specified, the values of step parameters or conditions are defaulted to be modified by "about".

[0193] In this application, unless the context clearly dictates otherwise, singular terms cover plural referents and vice versa.

[0194] This application also provides the following specific embodiments, but the protection scope of this application is not limited thereto:

[0195] Embodiment 1. A drug combination, which comprises an anti-CD40 antibody or an antigen-binding fragment thereof and a second therapeutic agent, wherein the second therapeutic agent is an anti-PD-1 antibody or an antigen-binding fragment thereof or a chemotherapeutic drug, and the anti-CD40 antibody or an antigen-binding fragment thereof comprises: an HCDR1 comprising the amino acid sequence shown in SEQ ID NO:1, an HCDR2 comprising the amino acid sequence shown in SEQ ID NO:2, an HCDR3 comprising the amino acid sequence shown in SEQ ID NO:3, an LCDR1 comprising the amino acid sequence shown in SEQ ID NO:4, an LCDR2 comprising the amino acid sequence shown in SEQ ID NO:5, and an LCDR3 comprising the amino acid sequence shown in SEQ ID NO:6.

[0196] Embodiment 2. The drug combination according to Embodiment 1, wherein the anti-CD40 antibody or an antigen-binding fragment thereof comprises:

[0197] a heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:9;

[0198] A heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:8, and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:9;

[0199] A heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:10;

[0200] A heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:8, and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:10;

[0201] The heavy chain variable region of the amino acid sequence shown in SEQ ID NO:7, and the light chain variable region of the amino acid sequence shown in SEQ ID NO:9;

[0202] The heavy chain variable region of the amino acid sequence shown in SEQ ID NO:8, and the light chain variable region of the amino acid sequence shown in SEQ ID NO:9;

[0203] The heavy chain variable region of the amino acid sequence shown in SEQ ID NO:7, and the light chain variable region of the amino acid sequence shown in SEQ ID NO:10; or

[0204] The heavy chain variable region of the amino acid sequence shown in SEQ ID NO:8, and the light chain variable region of the amino acid sequence shown in SEQ ID NO:10.

[0205] Embodiment 3. The pharmaceutical combination according to Embodiment 1 or 2, wherein the anti-CD40 antibody or its antigen-binding fragment comprises:

[0206] A heavy chain having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:11, and a light chain having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:13;

[0207] A heavy chain having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:12, and a light chain having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:13;

[0208] A heavy chain having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:11, and a light chain having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:14;

[0209] A heavy chain having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 12, and a light chain having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 14;

[0210] A heavy chain of the amino acid sequence shown in SEQ ID NO: 11, and a light chain of the amino acid sequence shown in SEQ ID NO: 13;

[0211] A heavy chain of the amino acid sequence shown in SEQ ID NO: 12, and a light chain of the amino acid sequence shown in SEQ ID NO: 13;

[0212] A heavy chain of the amino acid sequence shown in SEQ ID NO: 11, and a light chain of the amino acid sequence shown in SEQ ID NO: 14; or

[0213] A heavy chain of the amino acid sequence shown in SEQ ID NO: 12, and a light chain of the amino acid sequence shown in SEQ ID NO: 14.

[0214] Embodiment 4. The pharmaceutical combination according to any one of Embodiments 1-3, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises: an HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 15, an HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 16, an HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 17, an LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 18, an LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 19, and an LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 20.

[0215] Embodiment 5. The pharmaceutical combination according to any one of Embodiments 1-4, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises:

[0216] A heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 21, and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 22; or

[0217] A heavy chain variable region of the amino acid sequence shown in SEQ ID NO: 21, and a light chain variable region of the amino acid sequence shown in SEQ ID NO: 22.

[0218] Embodiment 6. The pharmaceutical combination according to any one of Embodiments 1-5, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises:

[0219] A heavy chain having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:23, and a light chain having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:24; or

[0220] The heavy chain of the amino acid sequence shown in SEQ ID NO:23, and the light chain of the amino acid sequence shown in SEQ ID NO:24.

[0221] Embodiment 7. The pharmaceutical combination according to any one of Embodiments 1-6, wherein the chemotherapeutic drug comprises anthracyclines; optionally, the anthracyclines comprise doxorubicin, epirubicin, pirarubicin, amrubicin, aclarubicin, idarubicin, daunorubicin, mitoxantrone, idamycin, valrubicin, zorubicin and / or pixantrone; optionally, the anthracyclines comprise doxorubicin.

[0222] Embodiment 8. The pharmaceutical combination according to any one of Embodiments 1-7, wherein the pharmaceutical combination comprises 10-800 mg, 20-500 mg, 30-300 mg or 60-200 mg of an anti-CD40 antibody or an antigen-binding fragment thereof.

[0223] Embodiment 9. The pharmaceutical combination according to any one of Embodiments 1-8, wherein the pharmaceutical combination comprises 10-800 mg, 50-500 mg, or 100-200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof or 25-150 mg / m2, 35-135 mg / m2, 50-90 mg / m2, or 50-75 mg / m2 of doxorubicin.

[0224] Embodiment 10. Use of the pharmaceutical composition according to any one of Embodiments 1-9 in the preparation of a drug for treating tumors.

[0225] Embodiment 11. The use according to Embodiment 10, wherein the tumor is soft tissue sarcoma or melanoma; optionally, the tumor is locally advanced, metastatic and / or recurrent soft tissue sarcoma or melanoma.

[0226] Embodiment 12. The use according to Embodiment 10 or 11, wherein the anti-CD40 antibody or an antigen-binding fragment thereof and the second therapeutic agent are each in the form of a pharmaceutical composition and can be administered simultaneously, successively and / or alternately.

[0227] Embodiment 13. The use according to any one of Embodiments 10 - 12, wherein the anti - CD40 antibody or its antigen - binding fragment is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks; and each time it is administered at a dose of 10 - 800 mg, 20 - 500 mg, 30 - 300 mg, or 60 - 200 mg.

[0228] Embodiment 14. The use according to any one of Embodiments 10 - 13, wherein the anti - PD - 1 antibody or its antigen - binding fragment is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks; and each time it is administered at a dose of 10 - 800 mg, 50 - 500 mg, or 100 - 200 mg.

[0229] Embodiment 15. The use according to any one of Embodiments 10 - 14, wherein the doxorubicin is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks; and each time it is administered at a dose of 25 - 150 mg / m2, 35 - 135 mg / m2, 50 - 90 mg / m2, or 50 - 75 mg / m2.

[0230] Embodiment 16. Use of an anti - CD40 antibody or its antigen - binding fragment and a second therapeutic agent in the preparation of a medicament for treating tumors, wherein the second therapeutic agent is an anti - PD - 1 antibody or its antigen - binding fragment or a chemotherapeutic drug, and the anti - CD40 antibody or its antigen - binding fragment comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO:1, HCDR2 comprising the amino acid sequence shown in SEQ ID NO:2, HCDR3 comprising the amino acid sequence shown in SEQ ID NO:3, LCDR1 comprising the amino acid sequence shown in SEQ ID NO:4, LCDR2 comprising the amino acid sequence shown in SEQ ID NO:5, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:6.

[0231] Embodiment 17. Use of an anti - CD40 antibody or its antigen - binding fragment in the preparation of a medicament for combined use with a second therapeutic agent for treating tumors, wherein the second therapeutic agent is an anti - PD - 1 antibody or its antigen - binding fragment or a chemotherapeutic drug, and the anti - CD40 antibody or its antigen - binding fragment comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO:1, HCDR2 comprising the amino acid sequence shown in SEQ ID NO:2, HCDR3 comprising the amino acid sequence shown in SEQ ID NO:3, LCDR1 comprising the amino acid sequence shown in SEQ ID NO:4, LCDR2 comprising the amino acid sequence shown in SEQ ID NO:5, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:6.

[0232] Embodiment 18. The use according to Embodiment 16 or 17, wherein the anti-CD40 antibody or antigen-binding fragment thereof comprises:

[0233] a heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:9;

[0234] a heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:8, and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:9;

[0235] a heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:10; or

[0236] a heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:8, and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:10;

[0237] the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:7, and the light chain variable region of the amino acid sequence shown in SEQ ID NO:9;

[0238] the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:8, and the light chain variable region of the amino acid sequence shown in SEQ ID NO:9;

[0239] the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:7, and the light chain variable region of the amino acid sequence shown in SEQ ID NO:10; or

[0240] the heavy chain variable region of the amino acid sequence shown in SEQ ID NO:8, and the light chain variable region of the amino acid sequence shown in SEQ ID NO:10.

[0241] Embodiment 19. The use according to any one of Embodiments 16-18, wherein the anti-CD40 antibody or antigen-binding fragment thereof comprises:

[0242] a heavy chain having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:11, and a light chain having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:13;

[0243] A heavy chain with an amino acid sequence having at least 90% identity to the amino acid sequence shown in SEQ ID NO:12, and a light chain with an amino acid sequence having at least 90% identity to the amino acid sequence shown in SEQ ID NO:13;

[0244] A heavy chain with an amino acid sequence having at least 90% identity to the amino acid sequence shown in SEQ ID NO:11, and a light chain with an amino acid sequence having at least 90% identity to the amino acid sequence shown in SEQ ID NO:14; or

[0245] A heavy chain with an amino acid sequence having at least 90% identity to the amino acid sequence shown in SEQ ID NO:12, and a light chain with an amino acid sequence having at least 90% identity to the amino acid sequence shown in SEQ ID NO:14;

[0246] The heavy chain of the amino acid sequence shown in SEQ ID NO:11, and the light chain of the amino acid sequence shown in SEQ ID NO:13;

[0247] The heavy chain of the amino acid sequence shown in SEQ ID NO:12, and the light chain of the amino acid sequence shown in SEQ ID NO:13;

[0248] The heavy chain of the amino acid sequence shown in SEQ ID NO:11, and the light chain of the amino acid sequence shown in SEQ ID NO:14; or

[0249] The heavy chain of the amino acid sequence shown in SEQ ID NO:12, and the light chain of the amino acid sequence shown in SEQ ID NO:14.

[0250] Embodiment 20. The use according to any one of embodiments 16 - 19, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO:15, HCDR2 comprising the amino acid sequence shown in SEQ ID NO:16, HCDR3 comprising the amino acid sequence shown in SEQ ID NO:17, LCDR1 comprising the amino acid sequence shown in SEQ ID NO:18, LCDR2 comprising the amino acid sequence shown in SEQ ID NO:19, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:20.

[0251] Embodiment 21. The use according to any one of embodiments 16 - 20, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises:

[0252] A heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 21, and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 22; or

[0253] The heavy chain variable region of the amino acid sequence shown in SEQ ID NO: 21, and the light chain variable region of the amino acid sequence shown in SEQ ID NO: 22.

[0254] Embodiment 22. The use according to any one of Embodiments 16-21, wherein the anti-PD-1 antibody or its antigen-binding fragment comprises:

[0255] A heavy chain having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 23, and a light chain having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO: 24; or

[0256] The heavy chain of the amino acid sequence shown in SEQ ID NO: 23, and the light chain of the amino acid sequence shown in SEQ ID NO: 24.

[0257] Embodiment 23. The use according to any one of Embodiments 16-22, wherein the chemotherapeutic drug comprises anthracyclines; optionally, the anthracyclines comprise doxorubicin, epirubicin, pirarubicin, amrubicin, aclarubicin, idarubicin, daunorubicin, mitoxantrone, idamycin, valrubicin, zorubicin, and / or pixantrone; optionally, the anthracyclines comprise doxorubicin.

[0258] Embodiment 24. The use according to any one of Embodiments 16-23, wherein the tumor is soft tissue sarcoma or melanoma; optionally, the tumor is locally advanced, metastatic, and / or recurrent soft tissue sarcoma or melanoma.

[0259] Embodiment 25. The use according to any one of Embodiments 16-24, wherein the anti-CD40 antibody or its antigen-binding fragment and the second therapeutic agent are each in the form of a pharmaceutical composition and can be administered simultaneously, successively, and / or alternately.

[0260] Embodiment 26. The use according to Embodiments 16-25, wherein the anti-CD40 antibody or its antigen-binding fragment is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks; each time it is administered at a dose of 10-800 mg, 20-500 mg, 30-300 mg, or 60-200 mg.

[0261] Embodiment 27. The use according to any one of Embodiments 16 - 26, wherein the anti - PD - 1 antibody or its antigen - binding fragment is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks; and each time it is administered at a dose of 10 - 800 mg, 50 - 500 mg, or 100 - 200 mg.

[0262] Embodiment 28. The use according to any one of Embodiments 16 - 27, wherein the doxorubicin is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks; and each time it is administered at a dose of 25 - 150 mg / m2, 35 - 135 mg / m2, 50 - 90 mg / m2, or 50 - 75 mg / m2.

[0263] For purposes of description and disclosure, all patents, patent applications, and other established publications are hereby expressly incorporated herein by reference. These publications are provided only because their disclosures predated the filing date of the present application. All statements as to the dates of these documents or the representation of the content of these documents are based on the information available to the applicant and do not constitute any admission as to the dates of these documents or the correctness of the content of these documents. Moreover, in any country, any reference to these publications in this application does not constitute an admission that such publication is part of the common general knowledge in the art. Examples

[0264] The present application will be further described below in conjunction with specific examples. However, these examples in the present application are only used for illustration and do not limit the scope of the present application. Similarly, the present application is not limited to any specific preferred embodiment described herein. Those skilled in the art should understand that equivalent substitutions or corresponding improvements made to the technical features of the present application still fall within the protection scope of the present application. Unless otherwise specified, the reagents used in the following examples are all commercially available products, and the preparation of solutions can adopt conventional techniques in the art.

[0265] Example 1: Clinical Trial

[0266] 1. Inclusion Criteria

[0267] Only those who meet all of the following inclusion criteria can be enrolled in this trial:

[0268] (1) The subject voluntarily joins this study, signs the informed consent form, and has good compliance.

[0269] (2) Age: 18 - 75 years old (at the time of signing the informed consent form); ECOG PS score: 0 - 1; the predicted survival period is more than 3 months.

[0270] (3) Patients with locally advanced or recurrent / metastatic soft tissue sarcoma and melanoma who are pathologically diagnosed and unable or refuse surgery and have no local treatment conditions. Cohort 1 includes the following subtypes: ① dedifferentiated liposarcoma, ② well-differentiated liposarcoma with dedifferentiated components, ③ leiomyosarcoma (except uterine leiomyosarcoma); Cohort 2 is undifferentiated pleomorphic sarcoma (limited to soft tissue sarcoma) and melanoma.

[0271] (4) Cohort 1: No history of failure of anthracycline chemotherapy (patients who receive anthracycline postoperative adjuvant chemotherapy and relapse or progress during or within 6 months after adjuvant treatment are considered to have failed anthracycline chemotherapy).

[0272] Cohort 2: Subjects with undifferentiated pleomorphic sarcoma have previously failed anthracycline chemotherapy or anti-angiogenic TKI treatment; subjects with melanoma have previously failed chemotherapy, PD-1 inhibitor treatment or targeted treatment (patients who receive postoperative adjuvant treatment and relapse or progress during or within 6 months after adjuvant treatment are considered to have failed first-line treatment).

[0273] Note: Treatment failure is defined as disease progression according to the RECIST 1.1 standard (immunotherapy requires the RECIST 1.1 standard and the iRECIST standard). Termination of treatment due to intolerance is not considered treatment failure.

[0274] (5) Cohort 2: Number of previous treatment lines: 1-2 (excluding postoperative adjuvant treatment, unless treatment failure occurs during or within 6

[0275] months after adjuvant treatment).

[0276] (6) Confirmed to have at least one measurable lesion according to the RECIST 1.1 standard.

[0277] (7) Good function of major organs, meeting the following criteria:

[0278] 1) Blood routine examination criteria (no blood transfusion and no use of hematopoietic stimulating factor drugs for correction within 7 days before screening):

[0279] a) Hemoglobin (HGB) ≥ 90 g / L;

[0280] b) Absolute neutrophil count (NEUT) ≥ 1.5 × 10 9 / L;

[0281] c) Platelet count (PLT) ≥ 85 × 10 9 / L.

[0282] 2) Biochemical examination needs to meet the following criteria (no corrective treatment within 7 days before screening):

[0283] a) Total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN);

[0284] b) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times ULN (if accompanied by liver metastasis, then

[0285] ALT, AST ≤ 5 times ULN);

[0286] c) Serum creatinine (CR) ≤ 1.5 times ULN or creatinine clearance rate (CCR) ≥ 60 mL / min (Cockcroft Gault formula).

[0287] 3) Coagulation function tests should meet the following criteria (without anticoagulant treatment):

[0288] a) Prothrombin time (PT) ≤ 1.5 times ULN;

[0289] b) Activated partial thromboplastin time (APTT) ≤ 1.5 times ULN;

[0290] c) International normalized ratio (INR) ≤ 1.5 times ULN;

[0291] 4) Echocardiogram assessment: Left ventricular ejection fraction (LVEF) ≥ 55%.

[0292] (8) Female subjects of childbearing age should agree to use contraceptive measures (such as intrauterine devices, contraceptives or condoms) during the study period and within 6 months after the end of the study; the serum pregnancy test should be negative within 7 days before study enrollment, and they must be non-lactating subjects; male subjects should agree to use contraceptive measures during the study period and within 6 months after the end of the study period.

[0293] 2. Test drugs

[0294] 2.1 huC1H1-V2 injection (specification: 16 mg / 1.6 mL / vial): One treatment cycle is 3 weeks. Administered by intravenous infusion, a dose of 60 mg, 100 mg or 200 mg of huC1H1-V2 is given once on the first day of each treatment cycle.

[0295] 2.2 Pamiparib injection (specification: 100 mg / 10 mL / vial): One treatment cycle is 3 weeks. Administered by intravenous infusion, a dose of 200 mg of pamiparib is given once on the first day of each treatment cycle.

[0296] 2.3 Doxorubicin hydrochloride for injection: One treatment cycle is 3 weeks. Administered by intravenous infusion, a dose of 75 mg / m 2 of doxorubicin is given once on the first day of each treatment cycle.

[0297] 3. Medication Regimen

[0298] Cohort 1: First, infuse huC1H1-V2 injection, and then administer doxorubicin hydrochloride for injection at least 30 minutes later.

[0299] Cohort 2: First, infuse huC1H1-V2 injection, and then administer penpulimab injection at least 30 minutes later.

[0300] 4. Adjustment of Administration Plan

[0301] huC1H1-V2 injection: Delayed administration is allowed, but the maximum delay time shall not exceed 12 weeks (calculated from the last administration time).

[0302] Penpulimab injection: Delayed administration is allowed, but the maximum delay time shall not exceed 12 weeks (calculated from the last administration time).

[0303] Doxorubicin hydrochloride for injection: Dose adjustment and delayed administration are allowed, and the maximum delay time for administration is not more than 9 weeks (calculated from the last administration time).

[0304] 5. Evaluation Criteria

[0305] Efficacy evaluation: According to RECIST 1.1, the iRECIST standard is used to confirm the efficacy at the same time.

[0306] Safety evaluation: The NCI-CTCAE 5.0 standard is used to judge the severity of adverse events.

[0307] 6. Endpoint Indicators

[0308] Objective response rate (ORR): It refers to the percentage of subjects with complete response (CR) or partial response (PR), and calculates the ratio of the number of objective response cases (PR + CR) to the total number of cases and the 95% confidence interval;

[0309] Disease control rate (DCR): It refers to the percentage of subjects with complete response (CR), partial response (PR) and stable disease (SD), and calculates the ratio of the number of disease control cases to the total number of cases and the 95% confidence interval;

[0310] Clinical benefit rate (CBR): It refers to the percentage of subjects with complete response (CR), partial response (PR) or stable disease (SD) for at least 6 months, and calculates the ratio of the number of clinical benefit cases to the total number of cases and the 95% confidence interval;

[0311] Duration of Response (DOR): For subjects with a best response of complete response (CR) or partial response (PR), it is defined as the time from the date of the first recorded tumor response to the date of the first recorded disease progression or the date of death due to any cause (whichever occurs first). The median DOR and its 95% confidence interval were evaluated using the Kaplan-Meier method, and a survival curve was plotted;

[0312] Progression-Free Survival (PFS): It refers to the time from the start of enrollment to the occurrence of objective disease progression or recurrence or death due to various causes (whichever occurs first). The median PFS and 95% confidence interval were evaluated using the Kaplan-Meier method, and a survival curve was plotted;

[0313] Overall Survival (OS): It refers to the time from the start of enrollment to death due to various causes. The median OS and 95% confidence interval were evaluated using the Kaplan-Meier method, and a survival curve was plotted;

[0314] 12-Month Progression-Free Survival Rate (12m-PFS): A survival curve was plotted using the Kaplan-Meier method, and the cumulative progression-free survival rate and its 95% confidence interval corresponding to a progression-free survival time of 12 months in the curve;

[0315] 6-Month Progression-Free Survival Rate (6m-PFS): A survival curve was plotted using the Kaplan-Meier method, and the cumulative progression-free survival rate and its 95% confidence interval corresponding to a progression-free survival time of 6 months in the curve;

[0316] Incidence of Adverse Events: The occurrence of all adverse events (AE), serious adverse events (SAE), and treatment-related adverse events (TRAEs), as well as abnormal laboratory test indicators;

[0317] Pharmacokinetics / Pharmacodynamics-Related Indicators: Pharmacokinetic (PK) parameters, incidence of immunogenicity (ADA), incidence of neutralizing antibodies (Nab), receptor occupancy (RO), etc.;

[0318] Detection of Treatment-Related Biomarkers: Such as the relationship between cytokine levels and PD-L1 expression levels and the efficacy, etc.

[0319] 7. Results

[0320] The results showed that huC1H1-V2 injection combined with pacritinib injection could effectively treat locally advanced, recurrent or metastatic soft tissue sarcoma (especially undifferentiated pleomorphic sarcoma) and melanoma, improve the clinical efficacy and survival benefit of patients, relieve and control the patient's condition, and slow down the progression of the disease. Exemplary patients who achieved partial response (PR) after treatment are shown below:

[0321] The patient was diagnosed with undifferentiated pleomorphic sarcoma. After surgical resection and postoperative chemotherapy (doxorubicin and ifosfamide), pulmonary metastasis occurred. Subsequently, the patient received combination therapy with huC1H1-V2 injection and penpulimab injection. On the first day of each treatment cycle, 100 mg of huC1H1-V2 and 200 mg of penpulimab were administered. With a treatment cycle of 21 days and continuous administration, after 4 treatment cycles, according to the efficacy evaluation criteria, the target lesion shrank by 37.5% compared to the baseline, and the efficacy was evaluated as PR (partial response).

[0322] Lesion status:

[0323] Screening period: Target lesion 16 mm

[0324] After 2 treatment cycles: Target lesion 13 mm (shrinking by 18.8%)

[0325] After 4 treatment cycles: Target lesion 10 mm (shrinking by 37.5%), and the efficacy was evaluated as PR.

[0326] The sequence information of this application is summarized in the following table:

[0327]

[0328]

[0329]

[0330] The preferred embodiments of this application have been described in detail. It should be understood that the application defined in the above paragraphs is not limited to the specific details set forth in the above description, because many obvious changes to this application are possible and do not depart from the spirit or scope of this application.

Claims

1. A pharmaceutical combination comprising an anti-CD40 antibody or an antigen-binding fragment thereof and a second therapeutic agent, wherein, The second therapeutic agent is an anti-PD-1 antibody or an antigen-binding fragment thereof or a chemotherapeutic drug, and the anti-CD40 antibody or an antigen-binding fragment thereof comprises: an HCDR1 comprising the amino acid sequence shown in SEQ ID NO:1, an HCDR2 comprising the amino acid sequence shown in SEQ ID NO:2, an HCDR3 comprising the amino acid sequence shown in SEQ ID NO:3, an LCDR1 comprising the amino acid sequence shown in SEQ ID NO:4, an LCDR2 comprising the amino acid sequence shown in SEQ ID NO:5, and an LCDR3 comprising the amino acid sequence shown in SEQ ID NO:

6.

2. The pharmaceutical combination according to claim 1, wherein, The anti-CD40 antibody or an antigen-binding fragment thereof comprises: a heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:9; a heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:8, and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:9; a heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:10; a heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:8, and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:10; a heavy chain variable region of the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region of the amino acid sequence shown in SEQ ID NO:9; a heavy chain variable region of the amino acid sequence shown in SEQ ID NO:8, and a light chain variable region of the amino acid sequence shown in SEQ ID NO:9; a heavy chain variable region of the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region of the amino acid sequence shown in SEQ ID NO:10; or a heavy chain variable region of the amino acid sequence shown in SEQ ID NO:8, and a light chain variable region of the amino acid sequence shown in SEQ ID NO:

10.

3. The pharmaceutical combination according to claim 1 or 2, wherein, The anti-CD40 antibody or an antigen-binding fragment thereof comprises: a heavy chain having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:11, and a light chain having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:13; a heavy chain having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:12, and a light chain having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:13; A heavy chain having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:11, and a light chain having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:14; A heavy chain having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:12, and a light chain having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:14; A heavy chain of the amino acid sequence shown in SEQ ID NO:11, and a light chain of the amino acid sequence shown in SEQ ID NO:13; A heavy chain of the amino acid sequence shown in SEQ ID NO:12, and a light chain of the amino acid sequence shown in SEQ ID NO:13; A heavy chain of the amino acid sequence shown in SEQ ID NO:11, and a light chain of the amino acid sequence shown in SEQ ID NO:14; or A heavy chain of the amino acid sequence shown in SEQ ID NO:12, and a light chain of the amino acid sequence shown in SEQ ID NO:

14.

4. The pharmaceutical combination according to any one of claims 1-3, wherein, The anti-PD-1 antibody or antigen-binding fragment thereof comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO:15, HCDR2 comprising the amino acid sequence shown in SEQ ID NO:16, HCDR3 comprising the amino acid sequence shown in SEQ ID NO:17, LCDR1 comprising the amino acid sequence shown in SEQ ID NO:18, LCDR2 comprising the amino acid sequence shown in SEQ ID NO:19, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:

20.

5. The pharmaceutical combination according to any one of claims 1-4, wherein, The anti-PD-1 antibody or antigen-binding fragment thereof comprises: A heavy chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:21, and a light chain variable region having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:22; or A heavy chain variable region of the amino acid sequence shown in SEQ ID NO:21, and a light chain variable region of the amino acid sequence shown in SEQ ID NO:

22.

6. The pharmaceutical combination according to any one of claims 1-5, wherein, The anti-PD-1 antibody or antigen-binding fragment thereof comprises: A heavy chain having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:23, and a light chain having an amino acid sequence with at least 90% identity to the amino acid sequence shown in SEQ ID NO:24; or A heavy chain of the amino acid sequence shown in SEQ ID NO:23, and a light chain of the amino acid sequence shown in SEQ ID NO:

24.

7. The pharmaceutical combination according to any one of claims 1-6, wherein, The chemotherapeutic agent comprises anthracyclines; optionally, the anthracyclines comprise doxorubicin, epirubicin, pirarubicin, amrubicin, aclarubicin, idarubicin, daunorubicin, mitoxantrone, idamycin, valrubicin, zorubicin, and / or pixantrone; optionally, the anthracyclines comprise doxorubicin.

8. The pharmaceutical combination according to any one of claims 1-7, wherein, The pharmaceutical combination comprises 10 - 800 mg, 20 - 500 mg, 30 - 300 mg or 60 - 200 mg of an anti-CD40 antibody or an antigen-binding fragment thereof.

9. The pharmaceutical combination according to any one of claims 1-8, wherein, The pharmaceutical combination comprises 10 - 800 mg, 50 - 500 mg, or 100 - 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof or 25 - 150 mg / m 2 , 35 - 135 mg / m 2 , 50 - 90 mg / m 2 , or 50 - 75 mg / m 2 of doxorubicin.

10. Use of the pharmaceutical composition according to any one of claims 1 - 9 for the preparation of a medicament for treating tumors.

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